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Big Data Analytics in Chemoinformatics
and Bioinformatics: With Applications

to Computer-Aided Drug Design,
Cancer Biology, Emerging Pathogens
and Computational Toxicology
Subhash C. Basak
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Big Data Analytics in
Chemoinformatics and
Bioinformatics
Big Data Analytics in
Bioinformatics
With Applications to Computer-Aided
Drug Design, Cancer Biology, Emerging
Pathogens and Computational
Toxicology
Edited by
Subhash C. Basak
Department of Chemistry and Biochemistry,
University of Minnesota, Duluth, MN,
United States
Marjan Vračko
Theory Department, Kemijski inštitut/National
Institute of Chemistry, Ljubljana, Slovenia
Preface
“We adore chaos because we love to produce order.”

—M.C. Escher
“. . .shall we stay our upward course? In that blessed region of Four Dimensions,
shall we linger at the threshold of the Fifth, and not enter therein? Ah, no! Let us
rather resolve that our ambition shall soar with our corporal ascent. Then, yielding
to our intellectual onset, the gates of the Six Dimension shall fly open; after that a
Seventh, and then an Eighth. . .”
—Edwin Abbott, In: Flatland
“I’m tired of sailing my little boat

Far inside of the harbor bar;
I want to be out where the big ships float—
Out on the deep where the Great Ones are!. . .

—Daisy Rinehart
In science there is and will remain a Platonic element which could not be taken
away without ruining it. Among the infinite diversity of singular phenomena
science can only look for invariants.
—Jacques Monod
We are currently living in an age when many spheres of science and life are
flushed with the explosion of big data. We are familiar with the term “data is the
new oil,” but often hear about information overload or data deluge. We need to sys-
tematically manage, model, interpret, visualize, and use such data in diverse
decision-support systems in basic research, technology, health care, and business, to
name just a few.
If we look at the main focus of this book—applications of big data analytics in
chemoinformatics, bioinformatics, new drug discovery, and hazard assessment of
environmental pollutants—, it is evident that data in all these fields are exploding.
Regarding the size of chemical space, the GDB-17 database contains 166.4 bil-
lion molecules containing up to 17 atoms of C, N, O, S, and halogens which fall
within the size range containing many drugs and are typical for druggable lead
compounds. The sequence data on DNA, RNA, and proteins are increasing each
day by new depositions by researchers worldwide. A simple combinatorial exercise
of sequence possibility for a 100-residue long protein suggests 20100 different possi-
ble sequences (considering 20 frequently occurring natural amino acids). Modern
computer software can calculate many hundreds, sometimes thousands of
xx Preface
descriptors for a molecule or a macromolecular sequence. The Vs of big data, viz.,

validity, vulnerability, volatility, visualization, volume, value, velocity, variety,
veracity, and variability, increase the complexity of big data analytics immensely.
Here, we come face to face with the stark reality of the curse of dimensionality
in the big data space of chemistry and biology. Following the parsimony principle,
we need to be careful in feature selection and use of robust validation techniques in
model building. Finally, analysis and visualization of models to understand their
meaning and derive actionable knowledge from the vast information space for prac-
tical implementation in the decision-support systems of science and society are of
paramount importance.
The first section, General Section, of the book has three chapters. Chapter 1
briefly traces the history of the development of chemodescriptors and biodescriptors
spanning three centuries—from the eighteenth century to the present. It is observed
by the author that the initial characterization of structures, both chemical and bio-
logical, were qualitative which was gradually followed by the development of quan-
titative chemodescriptors and biodescriptors. The author concluded that in the
socially and economically important areas of new drug discovery and hazard assess-
ment of chemicals use of a combined set of chemodescriptors and biodescriptors
for model building using big data would be a useful and practical paradigm.
Chapter 2 deals with the problem of robust model building from noisy high-
dimensional data, focusing primarily on the robustness aspects against data contam-
ination. The author also demonstrates the utility of his method in the prediction of
salmonella mutagenicity of a set of amines, a class priority pollutants. Chapter 3
delves into the ethical issues associated with the landscape of desirable qualities
such as fairness, transparency, privacy, and robustness of currently used machine
learning (ML) methods of big data analysis.
The second section, Chemistry and Chemoinformatics Section, of the book has
nine chapters. Chapter 4 discusses the use of big data in the characterization of
adverse outcome pathways (AOPs), a novel paradigm in toxicology. The author
integrated “big data”—the omics and high-throughput (HT) screening data—to
derive AOPs for chemical carcinogens. Chapter 5 discusses the latest progress in
the use of ML and DL (deep learning) methods in creating systems that automati-
cally mine patterns and learn from data. The author also discuss the challenges and
usefulness of DL for quantitative structure activity relationship (QSAR) modeling.
Chapter 6 describes retrosynthetic planning and analysis of organic compounds in
the synthetic space using big data sets and in silico algorithms. Chapter 7 discusses
that the vast amount of historical chemical information is not only a rich source of
data, but also a useful tool for studying the evolution of chemistry, chemoinfor-
matics, and bioinformatics through a computational approach to the history of
chemistry. The author exemplifies that by a case study of recent results on the
computational analysis of the evolution of the chemical space. Chapter 8 gives a
detailed description of combinatorial techniques useful in studying large data sets
with hypercubes and halocarbons as the main focus. Quantum chemical techniques
discussed here can generate electronic parameters that have potential for use in
QSAR for toxicity prediction of big data sets. Chapter 9 deals with the use of
Preface xxi
computed high-level quantum chemical descriptors derived from the density func-
tional theory in the prediction of property/toxicity of chemicals. Chapter 10 covers
the important area of the use of computed pharmacophores in practical drug design
from analysis of large databases. Chapter 11 uses ML based classification methods
for the detection of hot spots in protein protein interactions and prediction of new
hotspots. Chapter 12 discusses applications of decision tree methods like recursive
partitioning, phylogenetic-like trees, multidomain classification, and fuzzy cluster-
ing within the context of small molecule drug discovery from analysis of large
databases.
The third section, Bioinformatics and Computatioanl Toxicology Section, of the
book has seven chapters. Chapter 13 discusses their contributions in the emerging
area of mathematical proteomics approach in developing biodescriptors for the
characterization of bioactivity and toxicity of drugs and pollutants. Chapter 14 dis-
cusses the important role of efficient computational frameworks developed to cata-
log and navigate the protein space to help the drug discovery process. Chapter 15
discusses applications of ML and DL approaches to HT sequencing data in the
development of precision medicine using single-nucleotide polymorphisms as a tool
of reference. Chapter 16 discusses the development and use of a new class of
sequence comparison methods based on alignment-free sequence descriptors in the
characterization of emerging global pathogens like the Zika virus and coronaviruses
(SARS, MERS, and SARS-CoV-2). Chapter 17 discusses the important and emerg-
ing issue of different ways of building QSARs from large and diverse data sets that
can be continuously updated and expanded over time. The importance of modular-
ity in scalable QSAR system development is also discussed. Chapter 18 deals with
the applications of network analysis and big data to study interactions of drugs with
their targets in the biological systems. The authors point out that a paradigm shift
integrating big data and complex network is needed to understand the expanding
universe of drug molecules, targets, and their interactions. Finally, Chapter 19
reports the use of ML approaches consisting of supervised and unsupervised techni-
ques in the analysis of RNA sequence data of breast cancer to derive important bio-
logical insights. They were able to pinpoint some disease-related genes and proteins
in the breast cancer network.
Finally, we would like to specially mention that in drug research and toxicology,
we are witnessing an explosion of data, which are expressed by four principal Vs—
volume, velocity, variety, and veracity. However, the data per se is useless, the real
challenge is the transition to the last two steps on the three-step path to knowledge:
data information knowledge. When we talk about big data in drug research
and toxicology, we often think of omics data and in vitro data derived from HT
screening. On the other hand, a pool of high-quality “small” data exists, which has
been collected in the past. Under the label “small data” we have the standard toxi-
cological data based on well-defined toxic effects. A future challenge for us is to
integrate both data platforms—big and small—into a new and integrated knowledge
extraction system.
Subhash C. Basak
Marjan Vračko
List of contributors
Anshika Agarwal In silico Research Laboratory, Eminent Biosciences, Indore,

Madhya Pradesh, India
Sarah Albogami Department of Biotechnology, College of Science, Taif

University, Taif, Saudi Arabia
Nandadulal Bairagi Department of Mathematics, Centre for Mathematical

Biology and Ecology, Jadavpur University, Kolkata, West Bengal, India
Krishnan Balasubramanian School of Molecular Sciences, Arizona State

University, Tempe, AZ, United States
Subhash C. Basak Department of Chemistry and Biochemistry, University of

Minnesota, Duluth, MN, United States
Emilio Benfenati Laboratory of Environmental Chemistry and Toxicology, Istituto

di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
Apurba K. Bhattacharjee Department of Microbiology and Immunology,

Biomedical Graduate Research Organization, School of Medicine, Georgetown
University, Washington, DC, United States
Anushka Bhrdwaj In silico Research Laboratory, Eminent Biosciences, Indore,

Madhya Pradesh, India; Department of Bioinformatics, Computer Aided Drug
Designing and Molecular Modeling Lab, Alagappa University, Karaikudi, Tamil
Nadu, India
Suman K. Chakravarti MultiCASE Inc., Beachwood, OH, United States
Pratim Kumar Chattaraj Department of Chemistry, Indian Institute of

Technology Kharagpur, Kharagpur, West Bengal, India
Samrat Chatterjee Complex Analysis Group, Translational Health Science and

Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
xvi List of contributors
Ramana V. Davuluri Department of Preventive Medicine, Division of Health and

Biomedical Informatics, Northwestern University Feinberg School of Medicine,
Chicago, IL, United States
Tathagata Dey Centre for Interdisciplinary Research and Education, Kolkata,

West Bengal, India; Department of Computer Science & Engineering, Indian
Institute of Technology Bombay, Mumbai, Maharashtra, India
Abhik Ghosh Indian Statistical Institute, Kolkata, West Bengal, India
Indira Ghosh School of Computational & Integrative Sciences, Jawaharlal Nehru

University, New Delhi, Delhi, India
Giuseppina Gini Politecnico di Milano, DEIB, Piazza Leonardo da Vinci, Milano,

Italy
Lima Hazarika In silico Research Laboratory, Eminent Biosciences, Indore,

Guang Hu Department of Bioinformatics, Center for Systems Biology, School of

Biology and Basic Medical Sciences, Soochow University, Suzhou, P.R. China
Chiakang Hung Politecnico di Milano, DEIB, Piazza Leonardo da Vinci, Milano,

Italy
Tajamul Hussain Biochemistry Department, College of Science, King Saud

University, Riyadh, Saudi Arabia; Center of Excellence in Biotechnology Research,
College of Science, King Saud University, Riyadh, Saudi Arabia
Yanrong Ji Department of Preventive Medicine, Division of Health and

Biomedical Informatics, Northwestern University Feinberg School of Medicine,
Chicago, IL, United States
Isha Joshi In silico Research Laboratory, Eminent Biosciences, Indore, Madhya

Pradesh, India
Taushif Khan Immunology and Systems Biology Department, OPC-Sidra

Medicine, Ar-Rayyan, Doha, Qatar
Ravina Khandelwal In silico Research Laboratory, Eminent Biosciences, Indore,

Pawan Kumar National Institute of Immunology, Aruna Asaf Ali Marg, New
Delhi, Delhi, India
List of contributors xvii
Shivam Kumar Complex Analysis Group, Translational Health Science and

Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
Min Li Department of Bioinformatics, Center for Systems Biology, School of

Biology and Basic Medical Sciences, Soochow University, Suzhou, P.R. China
Jie Liao Department of Pathology, Northwestern University Feinberg School of

Medicine, Chicago, IL, United States
Claudiu N. Lungu Department of Chemistry, Faculty of Chemistry and

Chemical Engineering, Babes-Bolyai University, Cluj, Romania; Department
of Surgery, Faculty of Medicine and Pharmacy, University of Galati, Galati,
Romania
Subhabrata Majumdar AI Vulnerability Database, Seattle, WA, USA; Bias

Buccaneers, Seattle, WA, USA
Rama K. Mishra Department of Biochemistry and Molecular Genetics, Feinberg

School of Medicine, Northwestern University, Chicago, IL, United States
Manju Mohan In silico Research Laboratory, Eminent Biosciences, Indore,

Ashesh Nandy Centre for Interdisciplinary Research and Education, Kolkata, West
Bengal, India
Anuraj Nayarisseri In silico Research Laboratory, Eminent Biosciences, Indore,

Madhya Pradesh, India; Department of Bioinformatics, Computer Aided Drug
Nadu, India; Biochemistry Department, College of Science, King Saud University,
Riyadh, Saudi Arabia; Bioinformatics Research Laboratory, LeGene Biosciences
Pvt Ltd, Indore, Madhya Pradesh, India
Shahul H. Nilar Global Blood Therapeutics, San Francisco, CA, United States
Ranita Pal Advanced Technology Development Centre, Indian Institute of

Technology Kharagpur, Kharagpur, West Bengal, India
Aditi Pande In silico Research Laboratory, Eminent Biosciences, Indore, Madhya

Pradesh, India
Guillermo Restrepo Max Planck Institute for Mathematics in the Sciences,

Leipzig, Germany; Interdisciplinary Center for Bioinformatics, Leipzig University,
Leipzig, Germany
xviii List of contributors
Dipanka Tanu Sarmah Complex Analysis Group, Translational Health Science

and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
Dwaipayan Sen Centre for Interdisciplinary Research and Education, Kolkata,

West Bengal, India
Sanjeev Kumar Singh Department of Bioinformatics, Computer Aided Drug

Nadu, India
Chillamcherla Dhanalakshmi Srija In silico Research Laboratory, Eminent

Biosciences, Indore, Madhya Pradesh, India
Revathy Arya Suresh In silico Research Laboratory, Eminent Biosciences, Indore,

Muyun Tang Department of Bioinformatics, Center for Systems Biology, School

of Biology and Basic Medical Sciences, Soochow University, Suzhou, P.R. China
Garima Thakur In silico Research Laboratory, Eminent Biosciences, Indore,

Xin Tong Department of Pathology, Northwestern University Feinberg School of

Medicine, Chicago, IL, United States
Marjan Vracko Theory Department, Kemijski inštitut/National Institute of

Chemistry Ljubljana, Slovenia
Marjan Vračko National Institute of Chemistry, Hajdrihova 19, Ljubljana,

Slovenia; Theory Department, Kemijski inštitut/National Institute of Chemistry,
Ljubljana, Slovenia
Ze Wang Department of Pharmaceutical Sciences, Zunyi Medical University at

Zhuhai Campus, Zhuhai, P.R. China
DanDan Xu Department of Pathology, Northwestern University Feinberg School

of Medicine, Chicago, IL, United States
Guang-Yu Yang Department of Pathology, Northwestern University Feinberg

School of Medicine, Chicago, IL, United States
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Contents
List of contributors xv
Preface xix
Section 1 General section

1 Chemoinformatics and bioinformatics by discrete mathematics
and numbers: an adventure from small data to the realm of
emerging big data 3
Subhash C. Basak
1.1 Introduction 3
1.2 Chemobioinformatics—a confluence of disciplines? 5
1.2.1 Physical property: colligative versus constitutive 6
1.2.2 Early biochemical observations on the relationship
between chemical structure and bioactivity of molecules 6
1.2.3 Linear free energy relationship: the multiparameter
Hansch approach to quantitative structure activity
relationship 7
1.2.4 Chemical graph theory and quantum chemistry as the
source of chemodescriptors 9
1.3 Bioifnormatics: quantitative inforamtics in the age of big biology 19
1.4 Major pillars of model building 21
1.5 Discussion 24
1.6 Conclusion 27
Acknowledgment 29
References 29
2 Robustness concerns in high-dimensional data analyses and

potential solutions 37
Abhik Ghosh
2.1 Introduction 37
2.2 Sparse estimation in high-dimensional regression models 39
2.2.1 Starting of the era: the least absolute shrinkage and
selection operator 39
2.2.2 Likelihood-based extensions of the LASSO 40
2.2.3 Search for a better penalty function 41
2.3 Robustness concerns for the penalized likelihood methods 43
vi Contents
2.4 Penalized M-estimation for robust high-dimensional analyses 44

2.5 Robust minimum divergence methods for high-dimensional
regressions 46
2.5.1 The minimum penalized density power divergence
estimator 47
2.5.2 Asymptotic properties of the MDPDE under
high-dimensional GLMs 49
2.6 A real-life application: identifying important descriptors of
amines for explaining their mutagenic activity 51
2.7 Concluding remarks 54
Appendix: A list of useful R-packages for high-dimensional
data analysis 55
Acknowledgments 56
References 56
3 Fairness, explainability, privacy, and robustness for

trustworthy algorithmic decision-making 61
Subhabrata Majumdar
3.1 Introduction 61
3.2 Fairness in machine learning 61
3.2.1 Fairness metrics and definitions 62
3.2.2 Bias mitigation in machine learning models 63
3.2.3 Implementation 66
3.3 Explainable artificial intelligence 67
3.3.1 Formal objectives of explainable artificial intelligence 67
3.3.2 Taxonomy of methods 69
3.3.3 Do explanations serve their purpose? 71
3.4 Notions of algorithmic privacy 73
3.4.1 Preliminaries of differential privacy 74
3.4.2 Privacy-preserving methodology 76
3.4.3 Generalizations, variants, and applications 79
3.5 Robustness 81
3.5.1 Adversarial attacks 82
3.5.2 Defense mechanisms 83
3.5.3 Implementations 84
3.6 Discussion 84
References 84
Section 2 Chemistry & chemoinformatics section

4 How to integrate the “small and big” data into a complex
adverse outcome pathway? 99
Marjan Vračko
4.1 Introduction 99
Contents vii
4.2 State and review 101

4.3 Binding affinity to androgen nuclear receptor evaluated with
respect to carcinogenic potency data 104
4.4 Conclusion and future directions 106
References 111
5 Big data and deep learning: extracting and revising

chemical knowledge from data 115
Giuseppina Gini, Chiakang Hung and Emilio Benfenati
5.1 Introduction 115
5.2 Basic methods in neural networks and deep learning 117
5.2.1 Neural networks 117
5.2.2 Neural network learning 119
5.2.3 Deep learning and multilayer neural networks 120
5.2.4 Attention mechanism 123
5.3 Neural networks for quantitative structure activity relationship:
input, output, and parameters 124
5.3.1 Input 125
5.3.2 Chemical graphs and their representation 125
5.3.3 Output 127
5.3.4 Performance parameters 127
5.4 Deep learning models for mutagenicity prediction 128
5.4.1 Structure activity relationship and quantitative
structure activity relationship models for Ames test 129
5.4.2 Deep learning models for Ames test 130
5.5 Interpreting deep neural network models 134
5.5.1 Extracting substructures 137
5.5.2 Comparison of substrings with SARpy SAs 138
5.5.3 Comparison of substructures with Toxtree 139
5.6 Discussion and conclusions 144
5.6.1 A future for deep learning models 147
References 148
6 Retrosynthetic space modeled by big data descriptors 151

Claudiu N. Lungu
6.2 Computer-assisted organic synthesis 152
6.2.1 Retrosynthetic space explored by molecular descriptors
using big data sets 155
6.2.2 The exploration of chemical retrosynthetic space using
retrosynthetic feasibility functions 156
6.3 Quantitative structure activity relationship model 161
6.4 Dimensionality reduction using retrosynthetic analysis 164
6.5 Discussion 166
References 167
viii Contents
7 Approaching history of chemistry through big data on

chemical reactions and compounds 171
Guillermo Restrepo
7.2 Computational history of chemistry 172
7.2.1 Data and tools 173
7.3 The expanding chemical space, a case study for computational
history of chemistry 178
7.4 Conclusions 183
Acknowledgments 184
References 184
8 Combinatorial and quantum techniques for large data sets:

hypercubes and halocarbons 187
Krishnan Balasubramanian
8.2 Combinatorial techniques for isomer enumerations to
generate large datasets 189
8.2.1 Combinatorial techniques for large data structures 189
8.2.2 Möbius inversion 193
8.2.3 Combinatorial results 196
8.3 Quantum chemical techniques for large data sets 198
8.3.1 Computational techniques for halocarbons 198
8.3.2 Results and discussions of quantum computations and
toxicity of halocarbons 201
8.4 Hypercubes and large datasets 208
8.5 Conclusion 211
References 212
9 Development of quantitative structure activity relationship

models based on electrophilicity index: a conceptual DFT-based
descriptor 219
Ranita Pal and Pratim Kumar Chattaraj
9.2 Theoretical background 220
9.3 Computational details 221
9.4 Methodology 222
9.5 Results and discussion 223
9.5.1 Tetrahymena pyriformis 223
9.5.2 Tryphanosoma brucei 224
9.6 Conclusion 226
Acknowledgments 226
Conflict of interest 227
References 227
Contents ix
10 Pharmacophore-based virtual screening of large compound

databases can aid “big data” problems in drug discovery 231
Apurba K. Bhattacharjee
10.2 Background of data analytics, machine learning, intelligent
augmentation methods and applications in drug discovery 233
10.2.1 Applications of data analytics in drug discovery 233
10.2.2 Machine learning in drug discovery 233
10.2.3 Application of other computational approaches in
drug discovery 235
10.2.4 Predictive drug discovery using molecular modeling 236
10.3 Pharmacophore modeling 237
10.3.1 Case studies 241
10.4 Concluding remarks 243
References 244
11 A new robust classifier to detect hot-spots and null-spots in

protein protein interface: validation of binding pocket and
identification of inhibitors in in vitro and in vivo models 247
Yanrong Ji, Xin Tong, DanDan Xu, Jie Liao, Ramana V. Davuluri,
Guang-Yu Yang and Rama K. Mishra
11.2 Training and testing of the classifier 248
11.2.1 Variable selection using recursive feature elimination 249
11.2.2 Random forest performed best using both published and
combined datasets 249
11.3 Technical details to develop novel protein protein interaction
hotspot prediction program 251
11.3.1 Training data 251
11.3.2 Building and validating a novel classifier by evaluating
state-of-the-art feature selection and machine learning
algorithms 252
11.4 A case study 253
11.4.1 Identification of a druggable protein protein interaction
site between mutant p53 and its stabilizing chaperone
DNAJA1 using our machine learning-based classifier 253
11.4.2 Building the homology model of DNAJA1 and
optimizing the mutp53 (R175H) structure 254
11.4.3 Protein protein docking 255
11.4.4 Small molecules inhibitors identification through
drug-like library screening against the DNAJA1-
mutp53R175H interacting pocket 256
11.5 Discussion 259
Author contribution 260
x Contents
Acknowledgment 260
Conflicts of interest 260
References 260
12 Mining big data in drug discovery—triaging and decision trees 265

Shahul H. Nilar
12.2 Big data in drug discovery 265
12.3 Triaging 268
12.4 Decision trees 271
12.5 Recursive partitioning 271
12.6 PhyloGenetic-like trees 273
12.7 Multidomain classification 273
12.8 Fuzzy trees and clustering 276
Acknowledgments 278
References 278
Section 3 Bioinformatics and computatioanl toxicology

section
13 Use of proteomics data and proteomics-based biodescriptors in the
estimation of bioactivity/toxicity of chemicals and nanosubstances 285
Subhash C. Basak and Marjan Vracko
13.2 Proteomics technologies and their toxicological applications 286
13.2.1 Two-dimensional gel electrophoresis 286
13.2.2 Mass spectrometry-based proteomics technology and
their applications in mathematical nanotoxicoproteomics 290
13.3 Discussion 292
Acknowledgment 295
References 295
14 Mapping interaction between big spaces; active space from protein

structure and available chemical space 299
Pawan Kumar, Taushif Khan and Indira Ghosh
14.2 Background 301
14.2.1 Navigating protein fold space 301
14.2.2 From amino acid string to dynamic structural fold 301
14.2.3 Elements for classification of protein 303
14.2.4 Available methods for classifying proteins 303
14.3 Protein topology for exploring structure space 304
14.3.1 Modularity in protein structure space 305
14.3.2 Data-driven approach to extract topological module 306
Contents xi
14.4 Scaffolds curve the functional and catalytic sites 309

14.4.1 Signature of catalytic site in protein structures 311
14.4.2 Protein function-based selection of topological space 312
14.4.3 Protein dynamics and transient sites 315
14.4.4 Learning methods for the prediction of proteins and
functional sites 316
14.5 Protein interactive sites and designing of inhibitor 317
14.5.1 Interaction space exploration for energetically favorable
binding features identification 317
14.5.2 Protein dynamics guided binding features selection 317
14.5.3 Protein flexibility and exploration of ligand recognition site319
14.5.4 Artificial intelligence to understand the interactions of
protein and chemical 320
14.6 Intrinsically unstructured regions and protein function 321
14.7 Conclusions 322
Acknowledgments 323
References 323
15 Artificial intelligence, big data and machine learning approaches

in genome-wide SNP-based prediction for precision medicine and
drug discovery 333
Isha Joshi, Anushka Bhrdwaj, Ravina Khandelwal, Aditi Pande,
Anshika Agarwal, Chillamcherla Dhanalakshmi Srija, Revathy Arya Suresh,
Manju Mohan, Lima Hazarika, Garima Thakur, Tajamul Hussain,
Sarah Albogami, Anuraj Nayarisseri and Sanjeev Kumar Singh
15.2 Role of artificial intelligence and machine learning in medicine 334
15.3 Genome-wide SNP prediction 339
15.4 Artificial intelligence, precision medicine and drug discovery 340
15.5 Applications of artificial intelligence in disease prediction and
analysis oncology 343
15.6 Cardiology 345
15.7 Neurology 347
15.8 Conclusion 348
Abbreviations 350
References 351
16 Applications of alignment-free sequence descriptors in

the characterization of sequences in the age of big data:
a case study with Zika virus, SARS, MERS, and COVID-19 359
Dwaipayan Sen, Tathagata Dey, Marjan Vračko, Ashesh Nandy and
Subhash C. Basak
16.2 Section 1—bioinformatics today: problems now 362
16.2.1 What is bioinformatics and genomics? 362
xii Contents
16.2.2 Annotations 362

16.2.3 Evolution of sequencing methods 363
16.2.4 Alignment-free sequence descriptors 366
16.2.5 Metagenomics 367
16.2.6 Software development: scenario and challenges 368
16.2.7 Data formats 368
16.2.8 Storage and exchange 370
16.3 Section 2—bioinformatics today and tomorrow: sustainable
solutions 370
16.3.1 The need for big data 371
16.3.2 Software and development 373
16.4 Summary 383
References 384
17 Scalable quantitative structure activity relationship systems for

predictive toxicology 391
Suman K. Chakravarti
17.1 Background 391
17.2 Scalability in quantitative structure activity relationship
modeling 393
17.2.1 Consequences of inability to scale 394
17.2.2 Expandability of the training dataset 394
17.2.3 Efficiency of data curation 397
17.2.4 Ability to handle stereochemistry 398
17.2.5 Ability to use proprietary training data 398
17.2.6 Ability to handle missing data 398
17.2.7 Ability to modify the descriptor set 399
17.2.8 Scaling expert rule-based systems 399
17.2.9 Scalability of adverse outcome pathway-based
quantitative structure activity relationship systems 399
17.2.10 Scalability of the supporting resources 400
17.2.11 Scalability of quantitative structure activity
relationships validation protocols 401
17.2.12 Scalability after deployment 402
17.2.13 Ability to use computer hardware resources effectively 402
17.3 Summary 403
References 404
18 From big data to complex network: a navigation through the

maze of drug target interaction 407
Ze Wang, Min Li, Muyun Tang and Guang Hu
18.2 Databases 409
18.2.1 Chemical databases 409
18.2.2 Databases for targets 415
Contents xiii
18.2.3 Databases for traditional Chinese medicine 417

18.3 Prediction, construction, and analysis of drug target network 418
18.3.1 Algorithms to predict drug target interaction network 419
18.3.2 Tools for network construction 426
18.3.3 Network topological analysis 428
18.4 Conclusion and perspectives 430
Acknowledgments 431
References 431
19 Dissecting big RNA-Seq cancer data using machine learning to

find disease-associated genes and the causal mechanism 437
Dipanka Tanu Sarmah, Shivam Kumar, Samrat Chatterjee and
Nandadulal Bairagi
19.2 Bird’s eye view of the analysis of cancer RNA-Seq data
using machine learning 440
19.3 Materials and methods 441
19.3.1 Preprocessing of the data 441
19.3.2 Feature selection 441
19.3.3 Classification learning 442
19.3.4 Extraction of disease-associated genes 442
19.3.5 Validation 443
19.4 Hand-in-hand walk with RNA-Seq data 443
19.4.1 Dataset selection 443
19.4.2 Data preprocessing 444
19.4.3 Feature selection 445
19.4.4 Classification model 446
19.4.5 Identification of the genes involved in disease
progression 447
19.4.6 Significance of the identified deeply associated genes 447
19.5 Conclusion 451
References 451
Index 455
bioinformatics by discrete 1
mathematics and numbers: an
adventure from small data to the
realm of emerging big data
Subhash C. Basak
Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN,
United States
1.1 Introduction
“Oh, the thirst to know
how many!
The hunger
to know
how many
stars in the sky!

We spent
our childhood counting
stones and plants, fingers and
toes, grains of sand, and teeth,
our youth was past counting
petals and comets’ tails.
We counted
colors, years,
lives, and kisses;
in the country,
Big Data Analytics in Chemoinformatics and Bioinformatics. DOI: https://doi.org/10.1016/B978-0-323-85713-0.00028-1

© 2023 Elsevier Inc. All rights reserved.
4 Big Data Analytics in Chemoinformatics and Bioinformatics
oxen; by the sea,

the waves. Ships
became proliferating ciphers.
Numbers multiplied.”
Pablo Neruda, In: Ode to numbers
A currently emerging trend in many scientific disciplines is their tendency of

being gradually transformed/evolved into some form of information science (Basak
et al., 2015; Dehmer and Basak, 2012; Kerber et al., 2014). In the realm of che-
moinformatics and bioinformatics, in particular, methods of discrete mathematics
like graph theory, network theory, information theory etc. are gaining momentum
as useful tools in the representation, characterization, and comparison of molecular
and biological systems and their structures as well as in the prediction of property/
bioactivity/ toxicity of chemicals for new drug discovery and environmental protec-
tion (Basak, 1987, 2010, 2013a, 2014; Basak et al., 1988b, 2015; Bayda et al.,
2019; Bielinska-Waz et al., 2007; Braga et al., 2018; Chakravarti, 2021; Ciallella
and Zhu, 2019; Diudea et al., 2018; Gini et al., 2013; Guo et al., 2001; Kerber
et al., 2014; Khan et al., 2018; Nandy, 2015; Kier and Hall, 1986, 1999; Nandy
et al., 2006; Osolodkin et al., 2015; Randic et al., 2000, 2001, 2004, 2011; Restrepo
and Villaveces, 2013; Rouvray, 1991; Sabirov et al., 2021; Toropov and Toropova,
2021; Vračko et al., 2018, 2021a,b; Wang et al., 2021; Winkler et al., 2014).
The impetus for the development of chemoinformatics and bioinformatics tools/
methods has come from different directions. In new drug design, thousands of deri-
vatives of the initially discovered “lead” compound have to be synthesized and
tested in order to find one useful drug. This journey of the lead from the chemist’s
desk to the bedside of the patient involves a span of about 10 years and an expendi-
ture of over US$2 billion (DiMasi et al., 2016). Synthesis and testing of all possible
chemical derivatives of the identified lead compound is prohibitively costly. Under
such circumstances in silico approaches of chemoinformatics can give us fast and
cost-effective estimation of properties of promising derivatives of the lead chemi-
cals necessary for the prediction of the most probable pharmacological and toxico-
logical profiles (Table 1.1). Thus, chemoinformatics tools can assist the drug
designer as a decision support system. It has been noted that currently no drug is
developed without the prior evaluation by quantitative structureactivity relation-
ship (QSAR) methods (Santos-Filho et al., 2009).
The Toxic Substances Control Act (TSCA, 2021) Inventory, maintained by the
United States Environmental Protection Agency (USEPA), currently has more than
86,000 chemicals. Most of the TSCA chemicals have very little or no experimental
data required for their toxicity estimation. Detailed laboratory testing of all these
chemicals and their possible metabolites produced in the exposed organisms includ-
ing humans would be prohibitively costly. In the face of this lack of available data,
two approaches are used by the regulatory agencies: (a) class-specific QSAR mod-
els and (b) quantitative molecular similarity analysis (QMSA)-based modeling of
Chemoinformatics and bioinformatics by discrete mathematics and numbers 5
Table 1.1 A partial list of important physical, pharmacological, and toxicological

properties prerequisite to the evaluation of chemicals for new drug discovery and
environmental protection.
Physicochemical Pharmacological/toxicological
Molar volume Macromolecule level
Boiling point Receptor binding (KD)
Melting point Michaelis constant (Km)
Vapor pressure Inhibitor constant (Ki)
Water solubility DNA alkylation
Dissociation constant (pKa) Unscheduled DNA synthesis
Partition coefficient Cell level
Octanol-water (log P) Salmonella mutagenicity
Air-water Mammalian cell transformation
Sediment-water Organism level (acute)
Reactivity (electrophile) Algae
Invertebrates
Fish
Birds
Mammals
Organism level (chronic)
Bioconcentration
Carcinogenicity
Reproductive toxicity
Delayed neurotoxicity
Biodegradation
properties using structural analogs (Auer et al., 1990). The situation becomes more
numerous and complex if one considers the biotransformation and pharmacokinetic
data of the chemicals (TSCA metabolism and pharmacokinetics, 2021). A similar
situation exists in the European Union with the chemicals in commerce (European
Chemicals Agency, 2021) list showing more than 100,000 chemicals registered
with the system.
Table 1.1 provides a partial list of physicochemical, pharmacological, and toxi-
cological properties that drug designers and risk assessors of chemicals frequently
use in evaluating their beneficial and deleterious effects (Basak et al., 1990).
1.2 Chemobioinformatics—a confluence of disciplines?

“At quite uncertain times and places,
The atoms left their heavenly path,
And by fortuitous embraces,

Engendered all that being hath.
And though they seem to cling together,
And form “associations” here,
Yet, soon or late, they burst their tether,
And through the depths of space career.”

—James Clerk Maxwell
The current QSAR paradigm did not arise out of one or a few “aha” moments,
but it emerged through the confluence of a diverse set of ideas originated by quite a
few researchers of different disciplines over the past couple of centuries. For a
recent review, please see Basak (2021a). Some seminal aspects of the developments
of modern chemoinformatics are discussed as follows.
1.2.1 Physical property: colligative versus constitutive

“In order to describe an aspect of holistic reality we have to ignore certain factors
such that the remainder separates into facts. Inevitably, such a description is true
only within the adopted partition of the world, that is, within the chosen context.”
—Hans Primas (1981), Chemistry, Quantum Mechanics and Reductionism
In physical chemistry, a colligative property, for example, lowering of vapor

pressure, elevation of boiling point, depression of freezing point, and osmotic pres-
sure, of solutions is a property that depends solely upon the concentration of solute
molecules or ions, being independent of the constitution or identity of the solute.
Constitutive property, on the other hand, depends on the constitution or structure of
the substance. The American Heritage Dictionary of the English Language, 5th
Edition, states the following regarding the word constitutive:
“In physical chemistry, a term introduced by Ostwald to denote those properties of

a compound which depend on the constitution of the molecule, or on the mode of
union and arrangement of the atoms in the molecule.”
1.2.2 Early biochemical observations on the relationship

between chemical structure and bioactivity of molecules
For almost a century, various researchers in biochemistry and pharmacology gener-
ated data on the relation between the structure of molecules and their bioactivities.
Most probably one of the earliest was the 1928 finding of Quastel and Wooldridge
(1928) that malonic acid competitively inhibited the activity of the Krebs cycle
enzyme succinic dehydrogenase. Although the substrate succinic acid and the
inhibitor malonic acid differed by one methylene (CH2) group, the catalytic site
of the enzyme still recognized malonic acid. This seminal observation may be
looked upon as the rational basis for the synthesis of analogs of nucleic acid bases
for cancer chemotherapy (Hitchings and Elion, 1954) and the more modern che-
moinformatics approach to computer-aided drug design using the concept of phar-
macophore (Bhattacharjee, 2015). The antibiotic penicillin inhibits cell wall
biosynthesis in bacteria by interfering with the transpeptidation reaction responsible
for the crosslinking of mucopeptide chains in the cell wall polymer. This is attrib-
uted to its putative structural similarity to the D-alanyl-D-alanine portion of the
peptide chain (Goodman and Gilman, 1990).
1.2.3 Linear free energy relationship: the multiparameter Hansch

approach to quantitative structureactivity relationship
As described by Hansch and Leo (1979), in the early 1900s the English school of
organic chemists (Ingold, 1953) became interested in the mechanisms of reactions
of organic molecules. One approach was to make a set of structural modifications
in a parent molecule and then observe the effects of the substitutions on the rates or
equilibria of a reaction with a reactant under standard conditions. One could draw
conclusions about the electronic and steric requirements of a given reaction from
the analysis of the perturbations of the reaction center by the substituents. The pro-
blems of applications of these concepts, as indicated by Hansch and Leo (1979),
were:
“The difficulty with these early and important ideas was that no numerical scales
were available that could be used to quantify each of these effects that could
operate singly or in concert. Even when such scales had been devised, it was
difficult to make progress in the separation of substituent effects before high-
speed computers became generally available (approximately 1960).”
One important breakthrough in the field of mechanistic organic chemistry came

when Hammett (1937) proposed the now well-known Hammett equation. He
defined the parameter σ as follows:
σ 5 log Kx 2 log KH (1.1)
where KH is the ionization constant for benzoic acid in water at 25 C and Kx is the
ionization constant for its meta or para derivative under the same experimental con-
ditions. Positive values of σ indicate electron withdrawal by the substituent from
the aromatic ring and negative values represent electron release from the substituent
to the ring.
In the second half of the 20th century, Taft (1952) formulated the linear free
energy-related steric descriptor Es.
The multiparameter linear free energy relationship (LFER) approach, popularly
known as the “Hansch Analysis,” to quantitative structurepropertyactivity
relationship (QSPR/QSAR), derived from physical organic chemistry, attempted to

predict property/bioactivity of molecules using a combination of their electronic,
steric, and hydrophobic parameters (Hansch and Leo, 1995):
Log BA 5 a log P 1 bσ 1 c Es 1 constant ðlinearÞ (1.2)
log BA 5 a log P 1 b ðlog PÞ2 1 cσ 1 d Es 1 constant (1.3)
In Eq. (1.2), BA stands for biological activity, log P stands for the logarithm of
the partition coefficient (experimentally determined or calculated from structure) of
the chemical, σ usually represents Hammett’s (1937) electronic descriptor, and Es
usually symbolizes Taft’s steric parameter (Taft, 1952). A perusal of LEFR-based
QSAR models would indicate that different varieties of hydrophobic, steric, and
electronic parameters have been developed and used in numerous correlation stud-
ies (Hansch and Leo, 1995). A short description of the historical timeline for the
evolution of the LFER approach is depicted in Fig. 1.1.
The LFER approach gives good predictive models for congeneric sets of mole-
cules. As discussed above, both for drug design and hazard assessment of chemicals
Hansch approach 1962

bioactivity = f (Steric, electronic & hydrophobic parameters)
Taft steric parameter 1952 T

I
Hammett sigma 1937
Overton (1896) ; Meyer (1899)

Narcosis = f (oil-water partitioncoefficient) M
Crum-Brown & Fraser 1868: Prop = f (size, complexity) E
LFER Prop-prop correlation approach: P1 =f(P2)
Figure 1.1 A short history (1868-date) of the development of linear free energy relationship
approach for quantitative structureactivity relationship modeling based on physical
properties and substituent constants derived from physical organic chemistry. For more
information please see: Basak (2013a, 2021a) and Hansch and Leo (1995). In this approach,
a property (P1) of a molecule is estimated from another available property (P2) or a
combination of other properties.
we need to estimate the properties and bioactivities of chemicals which are structur-
ally diverse (Basak and Majumdar, 2016). Sometimes, one could wish to estimate
pharmacological and toxicological profiles of chemicals not yet synthesized.
Models based on the LFER-type experimental data are of little utility in such cases.
Furthermore, for applications in chemical engineering and technological processes
we need to know the values of many properties of substances (Drefahl and
Reinhard, 1998; Lyman et al., 1990). The use of good quality experimental property
values are always desirable, but such data are often unavailable. The use of QSAR-
predicted properties utilizing computed descriptors as the independent variables is
generally the practical alternative (Katritzky et al., 1995, 2001). More recently,
many large and diverse databases of properties needed for drug design and predic-
tive toxicology are becoming available in the public domain. These are resources
available for the development of broad-based models for property/bioactivity esti-
mation (Gadaleta et al., 2019; Mansouri et al., 2018; Meng et al., 2021).
During the second half of the 20th century and the first quarter of this century,
various chemoinformatics approaches have given us molecular descriptors which
can be computed directly from the molecular structure without the input of any
other experimental data. Such descriptors are finding side spread applications in the
formulation of useful QSAR models (Basak, 2021a, 2012b, 2013a, 2014; Drefahl
and Reinhard, 1998; Katritzky et al., 1995, 2001; Kier and Hall, 1986, 1999).
1.2.4 Chemical graph theory and quantum chemistry as the

source of chemodescriptors
“By convention sweet and by convention bitter, by convention hot, by convention
cold, by convention color; but in reality atoms and void.”
—Democritus
“The fundamental laws necessary for the mathematical treatment of a large part of
physics and the whole of chemistry are thus completely known, and the difficulty
lies only in the fact that application of these laws leads to equations that are too
complex to be solved.”
—Paul Dirac
1.2.4.1 Topological indices—graph theoretic definitions and

calculation methods
A graph, G, is defined as an ordered pair consisting of two sets V and R, G 5 [V
(G), R], where V(G) represents a finite nonempty set of points, and R is a binary
relation defined on the set V(G). The elements of V are called vertices and the ele-
ments of R, also symbolized by E(G) or E, are called edges. Such an abstract graph
is commonly visualized by representing elements of V(G) as points and by connect-
ing each pair (u, v) of elements of V(G) with a line if and only if (u, v)ER. The ver-
tex, v, and edge, e, are incident with each other, as are u and e. Two vertices u and
v in G are called adjacent if (u, v)ER, that is, they are connected by an edge. A walk
of a graph is a sequence beginning and ending with vertices in which vertices and
edges alternate and each edge is incident with vertices immediately preceding and
following it. A walk of the form v0, e1, v1, e2, . . ., vn joins vertices v0 and vn. The
length of a walk is the number of edges in the walk. A walk is closed if v0 5 vn,
otherwise it is open. A closed walk with n points is a cycle if all its points are dis-
tinct and n $ 3. A path is an open walk in which all vertices are distinct. A graph G
is connected if every pair of its vertices is connected by a path. A graph G is a mul-
tigraph if it contains more than one edge between at least one pair of adjacent verti-
ces, otherwise, G is a simple graph. The distance d (u, v) between vertices u and v
in G is the length of the shortest path connecting u and v.
Because of the general nature of graph-theoretic (GT) methods in the representa-
tion of objects this method has been used in such diverse areas as theoretical phys-
ics, chemistry, biological and social sciences, engineering, computer science and
linguistics (Harary, 1986). For example, GT has been used in the representation and
comparison of proteins, characterization of the nucleotide sequence topology in
DNA and RNA sequences (Nandy, 2015; Nandy et al., 2006; Randic et al., 2000,
2011), representation of protein spots of proteomics maps (Randić et al., 2001),
folding patterns in protein structures (Khan et al., 2018; Liu et al., 2006), structural
characterization of nanosubstances (Toropov and Toropova, 2021), to name just a
few.
For chemical graph theory research and applications (Basak, 2013a; Basak et al.,
2011; Janezic et al., 2015), a molecular graph represents molecular topology where
V represents the set of atoms and E usually symbolizes the set of covalent bonds
present in the molecule. It should be noted, however, that the set E should not be
limited to covalent bonds only. In fact, elements of E may symbolize any type of
bond, viz., covalent, ionic, or hydrogen bonds, etc. It was emphasized by Basak
et al. (1988a) that weighted pseudographs constitute a very versatile model for the
representation of a wide range of chemical species. Fig. 1.2 depicts the chemical
structure, labeled hydrogen-filled graph and labeled hydrogen-suppressed graph of
the molecule acetamide. It may be mentioned here that a large number of molecules
Figure 1.2 Structural formula (G0), labeled hydrogen-filled graph (G1), and labeled
hydrogen-suppressed graph (G2) of acetamide.
Another random document with
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Atterbury Plot. The details are somewhat obscure, and the
unravelling of them is complicated by the existence of another
scheme contemporaneous with Atterbury’s, apparently at first
independent, but which became merged in the larger design. The
author of this plot was Christopher Layer, a barrister of the Middle
Temple. Generally, his scheme was secretly to enlist broken and
discharged soldiers. They were to seize the Tower, the Bank, and the
Mint, and to secure the Hanoverian royal family, who were to be
deported. The larger scheme of the Junta was to obtain a foreign
force of 5000 troops to be landed in England under the Duke of
Ormonde, and risings were to be organised in different parts of the
kingdom. The signal for the outbreak was to be the departure of
George i. for Hanover, which was expected to take place in the
summer.
Layer, who does not seem to have been acting with Atterbury and
the Junta until later, was in Rome in the early months of 1721, and
there he unfolded his plan to the Jacobite Court. After he left, a plan
of campaign was arranged which, however, seems to have been
modified afterwards. The original intention was to begin the
movement in Scotland, whither Lord Mar and General Dillon[12] were
to proceed; and to accentuate the latter’s position as commander in
Scotland he was created an earl in the Scottish peerage, although
already an Irish (Jacobite) viscount. Lord Lansdowne was to
command in Cornwall, Lord Strafford in the north, Lord North in
London and Westminster, and Lord Arran was to go to Ireland. The
Chevalier was to leave Rome when Mar and Dillon left Paris, and to
make his way to Rotterdam via Frankfort, and there await events
before deciding where it would be best to land. Things seemed to be
prospering, but the English Jacobites did not sufficiently respond to
the call for financial support. James, deeply disappointed, appealed
to the Pope for help, only to be more bitterly mortified by his refusal.
The Pope, in so many words, said that if the English Jacobites
wanted a revolution they must pay for it themselves. The original
orders for invasion were cancelled in April; but negotiations seem to
have been continued with Spain through Cardinal Acquiviva,
Spanish envoy at Rome, ever James’s friend. A revised plan of
action was prepared. Wogan, who had been sent to Spain, had
succeeded in procuring assistance from that country; ships had been
prepared to carry a force of 5000 or 6000 men to Porto Longone, in
the Isle of Elba, where James was to embark. In July, James was on
the outlook for a Spanish fleet under Admiral Sorano.[13] But it was
too late. The plot had been discovered, the demand for troops
reaching the knowledge of the French ministers, who informed the
British ambassador. Spain was compelled to prevent the
embarkation, and King George did not go to Hanover that summer.
Mar had used the post office in spite of a warning by Atterbury
not to do so; his correspondence was intercepted, and a letter was
found which incriminated Atterbury and his associates. Government
was not hasty in acting, and the first conspirator to be arrested was
George Kelly, a Non-juring Irish clergyman who acted as Atterbury’s
secretary. He was seized at his lodgings on May 21st; and he very
nearly saved the situation. His papers and sword being placed in a
window by his captors, Kelly managed during a moment of
negligence to recover them. Holding his sword in his right hand he
threatened to run through the first man who approached him, while
all the time he held the incriminating papers to a candle with his left
hand, and not till they were burned did he surrender. It was not until
the end of August that Bishop Atterbury was taken into custody and
committed to the Tower. His trial did not begin until the spring of the
following year. Layer, who was betrayed by a mistress, was arrested
in September and tried in November. He was condemned to death,
but was respited from time to time in the hope that he would give
evidence to incriminate Atterbury and his associates. Layer refused
to reveal anything and was executed at Tyburn in May 1723, at the
very time when the bishop’s trial was taking place in the House of
Lords. Atterbury was found guilty: he was sentenced to be deprived
of all his ecclesiastical benefices and functions, to be incapacitated
from holding any civil offices, and to be banished from the kingdom
for ever. His associates of the Junta escaped with comparatively light
penalties. Kelly, sentenced to imprisonment during the King’s
pleasure, was kept in the Tower until 1736, when he managed to
escape, to reappear later in the drama. Atterbury went abroad and
entered the Chevalier’s service. He died in exile at Paris in 1732, but
he was buried in Westminster Abbey.
The failure of the schemes of Atterbury had a remarkable effect
on the unfortunate Chevalier. Apparently weary of failure and longing
for action, he wrote to the Pope on August 29th, 1722, offering to
serve in a crusade against the Turks; but he was told it would not do,
he must stick to his own task. To it he accordingly returned; and
implicitly believing that his people were longing for his restoration, he
issued a manifesto dated September 22nd, proposing ‘that if George
i. will quietly deliver to him the throne of his fathers he will in return
bestow upon George the title of king in his native dominions and
invite all other states to confirm it.’[14] The manifesto was printed and
circulated in England; it was ordered to be burned by the common
hangman.
It is somewhat remarkable that although the Atterbury Expedition
was to have been begun in Scotland, the records of the period make
no mention of the project, nor do there seem to have been any
preparations for a rising. The only suggestion of secret action being
taken that I know of—and it is no more than a suggestion—is that in
1721, on the same day that General Dillon, who was to command in
Scotland, was created a Scottish earl, a peerage was given to Sir
James Grant of Grant by the Chevalier de St. George.[15] What the
occasion of this honour may have been has never, so far as I know,
been revealed.[16]
Jacobite affairs in Scotland at that time were
administered by a Lanarkshire laird, George
Lockhart of Carnwath. Lockhart had been a Affairs in
member of the old Scots Estates before the Union Scotland.
of the kingdoms in 1707, and after the Union he sat in the Imperial
Parliament until 1715. In that year he raised a troop of horse for the
Jacobite cause, and after the rising he suffered a long imprisonment,
but was eventually released without trial. From 1718 to 1727 he
acted as the Chevalier’s chief confidential agent in Scotland. His
system of Jacobite management was by a body of trustees, which
was organised in 1722, and acted as a committee of regency for the
exiled king. In 1727 Lockhart’s correspondence fell into the hands of
Government and he had to fly the country. He was permitted to
return in the following year, but lived for the rest of his life in
retirement, and took no further part in Jacobite affairs.[17]
For some years after Lockhart’s flight, Scotland seems to have
been without any official representative of the Jacobite Court. In May
1736, however, Colonel James Urquhart[18] was appointed, though
under circumstances which have not yet been made known.
The proposed expedition connected with the Atterbury Plot was

the last project for an active campaign of restoration in which the
Chevalier was personally to embark. Scheming, of course, went on,
but only once after this did James leave Italy. In 1727, on the death
of George i., he hurried to Nancy to be ready for any emergency, but
the Duke of Lorraine had reluctantly to refuse him hospitality. He
retired to Avignon, but, as before, the British Government brought
pressure to bear, and he had to go back to Rome. Six years later, on
the death of Augustus the Strong, he was offered the elective throne
of Poland; but this he declined, saying that his own country engaged
his whole heart and all his inclinations, though he regretted that his
second son, Henry, then eight years old, was too young to be a
candidate for the crown worn by his Sobieski ancestor.
Meanwhile his elder son, Charles Edward, was Charles Edward

growing up, and the hopes of the party were fixed grows up.
on his future. His father wished him to learn the art
of war, so in August 1734 he was sent to join a
Spanish army under his cousin, the Duke of The Cause
Berwick,[19] who was engaged in the campaign languishes.
against Austria, which brought the crown of Naples
to the Spanish Bourbons. Charles, then not quite fourteen, took part
in the siege and capture of Gaeta, a fortress in Campania, and
accompanied Don Carlos in his triumphant entry into Naples as king
on August 9th. The Prince won much credit for his conduct in the
field, but this was the end of his experience of war, and his campaign
had lasted only six days. His father was anxious to extend his
military education, but France and Spain in turn declined to allow him
to serve with their armies. Even the Emperor, about to make war on
the Turks in 1737, refused to allow the young prince to accompany
his army. European potentates were unwilling to receive Charles
Edward even as a visitor. The Venetian minister in London was
ordered to quit England on twenty-four hours’ notice, because his
Government had shown civilities to the Prince on a visit to Venice.
The British Government was too vigilant to hoodwink, too strong to
offend. Peace reigned throughout Europe: Jacobite activity was
dormant both in England and in Scotland: the royal exiles were
isolated at Rome, and it seemed as if all hope of a Stuart Restoration
had been abandoned.
The first to inspire the Jacobite Court with new The Mission of
life and hope, and set in motion the events which Glenbucket.
led up to the great adventure of ’Forty-five was
John Gordon of Glenbucket. This remarkable man was no county
magnate nor of any particular family. At this time he possessed no
landed property; he was merely the tenant of a farm in Glenlivet,
which he held from the Duke of Gordon. His designation ‘of
Glenbucket’ was derived from a small property in the Don valley
which had been purchased by his grandfather, and which he
inherited from his father. He was not a Highlander, having been born
in the Aberdeenshire lowland district of Strathbogie, but he had so
thoroughly conformed himself to Highland spirit and manners that he
had won the affection and confidence of the Highlanders of
Banffshire and Strathspey. Glenbucket was at this time about sixty-
four years old. In his younger days he had been factor or
chamberlain to the Duke of Gordon, a position which conferred on
him considerable influence and power, particularly over the Duke’s
Highland vassals. In the ’Fifteen he had commanded a regiment of
the Gordon retainers, and behaved with gallantry and discretion
throughout the campaign.[20] About the year 1724 he had ceased to
be the Duke’s representative, but his connection with the
Highlanders was continued by the marriages of his daughters. One
of them was the wife of Forbes of Skellater, a considerable laird in
the Highland district of Upper Strathdon; another was married to the
great chief of Glengarry; and a third to Macdonell of Lochgarry.[21]
In the year 1737 Gordon sold Glenbucket, for which he realised
twelve thousand marks (about £700); and he left Scotland to visit the
Chevalier at Rome. On his way he passed through Paris, where he
had an interview with Cardinal Fleury, the French prime minister. To
the Cardinal he suggested a scheme of invasion, by which officers
and men of the Irish regiments in the French service quartered near
the coast could be suddenly and secretly transported to Scotland.[22]
The Cardinal, whose general policy was peace at any price,[23] gave
no encouragement to the scheme.
Glenbucket went on to Rome in January 1738: Message to the

he delivered his message, was rewarded with a English
major-general’s commission,[24] and returned to Jacobites.
Scotland. Immediately the Jacobite Court was filled
with sanguine activity. What the terms of Glenbucket’s mission were,
or whom he represented, have never been categorically stated.
Murray of Broughton hints that he only represented his son-in-law
Glengarry and General Alexander Gordon.[25] Even if this limitation
were true, it meant much. Glengarry was one of the greatest of
Highland chiefs, while General Gordon was that Nestor of Scottish
Jacobites who had been commander-in-chief after the Chevalier left
Scotland in 1716, and whose opinions must have carried much
weight. Although there is no direct statement of the terms of
Glenbucket’s mission, its significance can readily be understood
from the communication made to the English Jacobites. The
Chevalier at once wrote off to Cecil, his official agent in London,
informing him of the encouraging news he had received. The zeal of
his Scottish subjects, he said, was so strong that he considered it
possible to oppose the Scottish Highlanders to the greater part of the
troops of the British Government then available, and there was good
cause to hope for success even without foreign assistance, provided
the English Jacobites acted rightly.[26]
At the time that the Chevalier’s message reached his adherents
there happened to be in England a personage who bore the name
and designation of Lord Sempill.[27] Though of Scots descent he was
French by birth and residence. He was not familiar with English
ways, and he did not understand English political agitation. Mingling
for the most part with Jacobites avowed or secret, his ears were
filled with execration of the reigning dynasty. On every side he heard
the Whig Government denounced, and he saw it tottering and
vacillating. He mistook general political dissatisfaction for
revolutionary discontent, and he came to the conclusion that the
country longed for a restoration of the old royal line. Constituting
himself an envoy from the English Jacobites,[28] he hurried off to
Rome and reported to the Chevalier that the party was stronger than
was generally believed, and that affairs in England were most
favourable for action.
It is necessary here to relate how Glenbucket’s mission to Rome

affected the Scottish Jacobites, and to introduce into the narrative
the name of one who for five years was a mainstay of the Cause,
though in the end he turned traitor.
John Murray of Broughton, a younger son of Sir
David Murray of Stanhope (a Peeblesshire baronet
of ancient family who in his day had been an Murray of
ardent Jacobite), entered the University of Leyden Broughton.
in 1735, being then twenty years of age. In 1737 he had completed
his studies and went on a visit to Rome, where he mixed in the
Jacobite society of the place. Although he never had an interview
with James himself, he frequently met the young princes, and he
acquired the friendship of James Edgar, the Chevalier’s faithful
secretary. Murray’s father had once been proposed as an official
Jacobite agent in Scotland, and it seems highly probable that Edgar
persuaded the son to look forward to assuming such a position.
Murray left Rome to return to Scotland shortly before Glenbucket’s
arrival in January 1738.
Glenbucket’s message had convinced James of
the devotion of the Highlanders and the Jacobites
of north-eastern Scotland, but he wished to know The Concert of
more of the spirit of the Scottish Lowlands. At the Scots Jacobites.
same time that he wrote to the English Jacobites, he despatched
William Hay, a member of his household, to Scotland to make
inquiries and to report. Hay overtook Murray who was lingering in
Holland, and induced him to accompany him, as he was anxious to
be introduced to Murray’s cousin, Lord Kenmure, an ardent
Kirkcudbrightshire Jacobite. The acquaintance was duly made, and
although no record is yet known of Hay’s actual transactions in
Scotland, they can be conjectured with a fair amount of certainty
from the results which followed them in spite of Murray’s disparaging
remarks on his mission.[29] Hay visited the leading Jacobites, and it
is difficult to doubt that he set in motion a scheme for concerted
action. What is known is that he returned to Rome after three
months’ absence greatly satisfied with what he had found. In the
same year, presumably as the outcome of Hay’s mission, an
Association of Jacobite leaders was formed, sometimes termed ‘the
Concert,’ designed with the object of bringing together Highland
chiefs and lowland nobles,[30] pledged to do everything in their
power for the restoration of the exiled Stuarts. These Associators, as
they were called, were: the Duke of Perth; his uncle, Lord John
Drummond; Lord Lovat; Lord Linton, who in 1741 succeeded as fifth
Earl of Traquair; his brother, the Hon. John Stuart; Donald Cameron,
younger of Lochiel; and his father-in-law, Sir John Campbell of
Auchenbreck, an Argyllshire laird. The position of manager was
given to William Macgregor (or Drummond), the son of the
Perthshire laird of Balhaldies.[31] In contemporary documents
Macgregor[32] is generally termed ‘Balhaldy,’[33] and that designation
has been used in this volume. Murray of Broughton did not belong to
the Association, nor was he taken into its confidence until 1741. He,
however, attached himself to Colonel Urquhart, the official Jacobite
agent, and assisted him with his work. In 1740, when Urquhart was
dying of cancer, Murray was appointed to succeed him.
In December 1739 Balhaldy was sent by the Associators to Paris,
and from thence he went on to Rome. The Chevalier, greatly
cheered by what he had to tell, instructed him to return to Paris and
there to meet Sempill, who had become one of James’s most trusted
agents. Sempill would introduce him to Cardinal Fleury, before whom
they would lay the views of both the English and Scottish Jacobites.
Balhaldy returned to Paris, made the acquaintance of Sempill, an
acquaintance which subsequently ripened into a strong political,
perhaps personal, friendship. The interview with Fleury was
obtained, and negotiations commenced in the beginning of 1740,
about three months after the war with Spain, forced upon Walpole,
had broken out.[34]
It is no part of my task to follow the intricacies of the negotiations
between the French Ministry and the English Jacobites, except when
they affect the affairs of the Scots, but here it is necessary to turn
back for a moment to relate what took place after the English
Jacobites received the Chevalier’s communication of Glenbucket’s
message from Scotland.
Sempill, who had gone from England to Rome English

in the spring of 1738, was sent back in October reception of
with the Chevalier’s instructions to his English Scots
adherents to arrange for concerted action with the Proposals.
Scots. The English Jacobites formed a council of
six members to serve as a directing nucleus. This council
communicated the English views on the Scottish proposal to the
Chevalier as follows. Although the Government, they said, had only
29,000 regular troops in the British Isles, of which 13,000 were in
England, 12,000 in Ireland, and 4000 in Scotland, yet the rising of
the Scots could not take place, as the King hoped, without foreign
assistance. It would be a difficult matter to provide the Scots with
sufficient arms and munitions, and even if this difficulty could be
surmounted, it would take two months after they had been supplied
before their army could assemble and establish the royal authority in
Scotland; that it would take another month before the Scots could
march into England. Meantime the English leaders would be at the
mercy of the professional army of the Government which their
volunteer followers, entirely ignorant of discipline, could never
oppose alone. The principal royalists would be arrested in detail, and
their overawed followers would hold back from joining the Scots.
There were 13,000 regular soldiers in England. Government would
probably transfer 6000 from Ireland, and the army would be further
augmented by the importation of Dutch and Hanoverian troops.
Probably 8000 men would be sent to the frontier of Scotland. From
this they concluded that a rising in Scotland without foreign
assistance would involve possible failure and in any case a
disastrous civil war, while, on the other hand, the landing of a body of
regular troops would provide a rallying point for the insurgents. This
force should be equal to the number of troops generally quartered
about London and able to hold them, while the volunteer royalists
would march straight to the capital which was ready to declare in
their favour. They would then acquire the magazines and arsenals at
the seat of government, and almost all the treasures of England
(‘presque toutes les richesses d’Angleterre’). If at that juncture the
Scots would rise, the Hanoverians would be driven to despair. No
ally of the Elector, however powerful, would venture to attack Great
Britain reunited under her legitimate sovereign. The requirement of
the English would be 10,000 to 12,000 regular troops sent from
abroad; without such a disciplined force the English Jacobites would
not risk a rising.[35]
Sempill was sent by the Chevalier to Paris to lay these views
before Cardinal Fleury. The Cardinal, peace lover though he was, felt
that it would be absurd to neglect the assistance that the Jacobites
might afford him in the complications which were certain to arise
when the death of the Emperor Charles vi., then imminent, should
occur.[36] When the English views of requirement were presented to
him he received them sympathetically; said that the King of France
would willingly grant the help the English Jacobites desired, but two
things were absolutely necessary: he must have more exact
information than had been given him with regard to what royalist
adherents would join his troops on landing, and also as to those who
would rise at the same time in the provinces. If the English leaders
could satisfy His Majesty on these two points they might expect all
they asked for.[37]
Such was the state of Jacobite affairs at the Balhaldy’s

French Court when Sempill introduced Balhaldy to interview with
Fleury. I know of no categorical statement of the Fleury.
requirements that Balhaldy was to lay before the
Cardinal, but from a memorandum he wrote[38] it may be inferred
that the Associators had asked for 1500 men with arms, ammunition,
and money. Fleury replied that his sovereign was greatly pleased
with the proposals of the Scots, and that he approved of their
arrangements on behalf of their legitimate king. France, however,
was at peace with Great Britain, while Spain was at open war. King
Louis would ask the Spanish Court to undertake an expedition in
favour of King James to which he would give efficient support.[39]
Shortly afterwards, the Cardinal was obliged to tell Balhaldy that
Spain declined to entertain the proposal. The Spanish Court disliked
the war with England, and was quite aware that it had been forced
on Walpole by the Jacobites and the Opposition.[40] Spain was not
going to embarrass the British Government by embarking on a
Jacobite adventure.
Fleury then made a proposal that the Spanish Government
should finance a scheme by which an army of 10,000 Swedish
mercenaries should be engaged to invade Great Britain. While
secret negotiation was going on between the French and Spanish
Governments, knowledge of the proposal came to Elizabeth
Farnese, Queen of Spain. Elizabeth, fearing that a successful
movement for a Stuart restoration would put an end to the war with
Great Britain which she strongly favoured, inspired a paragraph in
the Amsterdam Gazette, which exploded the design before it could
be accomplished.[41]
Driven at last from his hope of using Spain as a catspaw, Fleury
informed Balhaldy that his master the King, touched with the zeal of
the Scots, would willingly send them all the Irish troops in his service,
with the arms, munitions, and the £20,000 asked for to assist the
Highlanders.[42]
Balhaldy hurried back to Scotland with this promise and met the
Associators in Edinburgh. Although the Jacobite leaders were
disappointed that French troops were not to be sent, they gratefully
accepted Fleury’s assurances, and in March 1741 they despatched
the following letter to the Cardinal, which was carried back to Paris
by Balhaldy.
Monseigneur,—Ayant appris de Monsieur
le baron de Balhaldies l’heureux succès des
représentations que nous l’avions chargé de Lettre de
faire à Votre Eminence sous le bon plaisir de quelques
Seigneurs
notre souverain légitime, nous nous hâtons de écossais au
renvoyer ce baron avec les témoignages de Cardinal de
notre vive et respectueuse reconnaissance et Fleury.[43]
avec les assurances les plus solennelles, tant
de notre part que de la part de ceux qui se sont engagés
avec nous à prendre les armes pour secouer le joug de
l’usurpation, que nous sommes prêts à remplir fidèlement
tout ce qui a été avancé dans le mémoire que my lord
Sempill et ledit sieur baron de Balhaldies eurent l’honneur
de remettre, signé de leurs mains, entre celles de Votre
Eminence au mois de mai dernier.
Les chefs de nos tribus des montagnes dont les noms
lui ont été remis en même temps avec le nombre
d’hommes que chacun d’eux s’est obligé de fournir,[44]
persistent inviolablement dans leurs engagements et nous
osons répondre à Votre Eminence qu’il y aura vingt mille
hommes sur pied pour le service de notre véritable et
unique seigneur, le Roi Jacques Huitième d’Ecosse
aussitôt qu’il plaira à S.M.T.C. de nous envoyer des armes
et des munitions avec les troupes qui sont nécessaires
pour conserver ces armes jusqu’à ce que nous puissions
nous assembler.
Ces vingt mille hommes pourront si facilement chasser
ou détruire les troupes que le gouvernement présent
entretient actuellement dans notre pays et même toutes
celles qu’on y pourra faire marcher sur les premières
alarmes que nous sommes assurément bien fondés
d’espérer qu’avec l’assistance divine et sous les auspices
du Roi Très Chrétien les fidèles Ecossais seront en état,
non seulement de rétablir en très peu de temps l’autorité
de leur Roi Légitime dans tout son royaume d’Ecosse et
de l’y affermir contre les efforts des partisans d’Hannover,
mais aussi de l’aider puissamment au recouvrement de
ces autres Etats, ce qui sera d’autant plus facile que nos
voisins de l’Angleterre ne sont pas moins fatigués que
nous de la tyrannie odieuse sous laquelle nous gémissons
tous également et que nous savons qu’ils sont très bien
disposés à s’unir avec nous ou avec quelque puissance
que ce soit qui voudra leur donner les recours dont ils out
besoin pour se remettre sous un gouvernement légitime et
naturel. Nous prenons actuellement des mesures pour
agir de concert avec eux.
Quant au secours qui est nécessaire pour l’Ecosse en
particulier, nous aurions souhaité que S.M.T.C. eût bien
voulu nous accorder des troupes françaises qui eussent
renouvelé parmi nous les leçons d’une valeur héroïque et
d’une fidélité incorruptible que nos ancêtres ont tant de
fois apprises dans la France même; mais puisque V.E.
juge à propos de nous envoyer de sujets de notre Roi,
nous les recevrons avec joie comme venant de sa part, et
nous tâcherons de leur faire sentir le cas que nous faisons
et de leur attachement à notre souverain légitime et de
l’honneur qu’ils out acquis en marchant si longtemps sur
les traces des meilleurs sujets et des plus braves troupes
en l’Univers.
Monsieur le baron de Balhaldies connaît si
parfaitement notre situation, les opérations que nous
avons concertées, et tout ce qui nous regarde, qu’il serait
inutile d’entrer ici dans aucun détail. Nous supplions V.E.
de vouloir bien l’écouter favorablement et d’être
persuadée qu’il aura l’honneur de lui tout rapporter dans la
plus exacte vérité.
Si les ministres du gouvernement étaient moins jaloux
de nos démarches ou moins vigilants, nous engagerions
volontiers tous nos biens pour fournir aux frais de cette
expédition; mais nuls contrats n’étant valables, suivant
nos usages, sans être inscrits sur les registres publics, il
nous est impossible de lever une somme tant soit peu
considérable avec le secret qui convient dans les
circonstances présentes. C’est uniquement cette
considération qui nous empêche de faire un fond pour les
dépenses nécessaires, [ce qui serait une preuve ultérieure
que nous donnerions avec joie de notre zèle et de la
confiance avec laquelle nous nous rangeons sous
l’étendard de notre Roi naturel; mais le bien du service
nous oblige de nous contenir et] d’avoir recours à la
générosité de S.M.T.C. jusqu’à ce que l’on puisse lever les
droits royaux dans notre pays d’une manière régulière.
Nous sommes persuadés que l’on pourra y parvenir
dans l’espace de trois mois après l’arrivée des troupes
irlandaises et nous ne doutons point que notre patrie,
réunie alors sous le gouvernement de son Roi tant désiré
ne fasse des efforts qui donneront lieu à V.E. de prouver à
S.M.T.C. que les Ecossais modernes sont les vrais
descendants de ceux qui ont eu l’honneur d’être comptés
pendant tant de siècles les plus fidèles alliés des Rois,
ses prédécesseurs.
Nous sommes bien sensiblement touchés des
mouvements que V.E. s’est donnés et qu’elle veut bien
continuer pour faire entendre au Roi Catholique les
avantages qu’il y aurait à agir en faveur du Roi notre
maître dans la conjoncture présente. Nous avions cru que
ces avantages ne pouvaient échapper aux ministres
Espagnols; mais quelque travers qu’ils prennent dans la
conduite de cette guerre, V.E. prend une part qui ne saura
manquer de les en tirer heureusement et de frustrer
l’attente injuste des nations qui sont prêtes à fondre sur
les trésors du nouveau monde.
Nous en louons Dieu, Monseigneur, et nous le prions
avec ferveur de vouloir bien conserver V.E. non seulement
pour l’accomplissement du grand ouvrage que nous allons
entreprendre sous sa protection mais aussi pour en voir
les grands et heureux effets dans toute l’Europe aussi
bien que dans les trois royaumes britanniques, auxquels
son nom ne sera pas moins précieux dans tous les temps
à venir qu’à la France même qui a pris de si beaux
accroissements sous son ministère et dont la gloire va
être élevée jusqu’au comble en faisant vigorer la justice
chez ses voisins. Nous avons l’honneur d’être avec une
profonde vénération et un parfait dévouement,
Monseigneur, de votre Eminence, les très humbles et très
obéissants serviteurs,
Le duc de Perth
Le lord Jean Drumond de
Perth
My lord Lovat
Milord Linton
Cameron, baron de Locheil
Le chevalier Campbell
D’Achinbreck
M’Grieger baron de
Balhaldies.
à Edimbourg, ce 13ème Mars 1741.
[Translation.]
Having learned from the Baron of Balhaldies of the
happy success of the representations that we had
instructed him to make to Your Eminence, with the
approval of our legitimate Sovereign, we now hasten to
send this Baron back with the proofs of our lively and
respectful gratitude, and with the most solemn
undertaking, both by ourselves and by those who are
engaged along with us, to take up arms to throw off the
yoke of the usurpation, that we are ready to fulfil faithfully
all that was put forward in the Memorial, which my lord
Sempill and the said Baron of Balhaldies signed with their
own hands, and had the honour to place in the hands of
Your Eminence last May.
The chiefs of our Highland clans, whose names we
have sent at the same time with the number of men that
each binds himself to furnish, will without fail keep their
engagements, and we venture to be responsible to Your
Eminence that there will be 20,000 men on foot for the
service of our true and only lord, King James viii. of
Scotland, as soon as it will please His Most Christian
Majesty to send us arms and munitions, and the troops
that are necessary to guard those arms until we shall be
able to assemble.
These 20,000 men will be able so easily to defeat or to
destroy the troops that the Government employs at
present in our country, and even all those that it may be
able to despatch upon the first alarm, so that we feel
entirely justified in hoping that with divine assistance and
under the auspices of the most Christian King, the loyal
Scots will be in a condition, not only in a short time to re-
establish the authority of their legitimate King throughout
the whole Kingdom of Scotland, and to sustain him there
against the efforts of the partisans of Hanover, but also to
aid powerfully in the recovery of these other States, which
will be all the easier since our neighbours of England are
not less wearied than we are of the odious tyranny under
which we all equally groan; and we know that they are
thoroughly determined to unite with us, and with any
power whatever that would give them the opportunity they
require to place themselves once more under a legitimate
and natural Government. We are at present taking
measures to act along with them.
As to the assistance that is necessary for Scotland in
particular, we should have preferred that His Most
Christian Majesty might have been willing to grant us
French troops, who would have renewed among us the
lessons of heroic bravery and incorruptible fidelity, that our
ancestors have so often learned in France itself, but since
Your Eminence thinks fit to send subjects of our King, we
will receive them with joy as coming from him, and we will
endeavour to make them feel the value that we attach to
their devotion to our legitimate Sovereign, and the honour
that they have acquired in treading so long in the footsteps
of the best subjects and of the bravest troops in the
Universe.
The Baron of Balhaldies knows so perfectly our
situation, the plans that we have concerted, and
everything that affects us, that it will be unnecessary to
enter into any detail. We implore Your Eminence to listen
to him favourably, and to be assured that he will have the
honour of reporting to you with the utmost accuracy.
If the ministers of the Government were only less
suspicious of our actions or less watchful, we would
willingly pledge all our belongings to defray the cost of this
expedition, but as no contracts (of loan or sale) are
binding by our customs unless they have been inscribed in
the public registers, it is not possible for us to raise a sum
that would be sufficient, with the necessary secrecy that
present circumstances require. It is this consideration
alone that prevents us from raising a fund for the
necessary expense, the raising of which would bear
further proof of our zeal, which we should give with
pleasure, and of the confidence with which we place
ourselves under the standard of our natural King; but the
good of the service obliges us to restrain our wishes and
to have recourse to the generosity of His Most Christian
Majesty until it is possible to establish the royal rights in
our country in a regular manner.
We are persuaded that it would be possible to
accomplish this three months after the arrival of the Irish
troops, and we do not doubt that our country, reunited
under the Government of its king, so much desired, would
make such efforts as would enable Your Excellency to
prove to His Most Christian Majesty that the modern Scots
are the true descendants of those who have had the
honour of being counted during so many centuries the
most faithful allies of the kings, his predecessors.
We are very sensibly touched by what Your Eminence
has done, and will continue to do, to make the Catholic
king understand the advantages that he would have in
acting in favour of the King our master in the present
juncture. We had believed that these advantages could
not escape the notice of the Spanish Ministers, but
whatever strange things they may have done in the
conduct of this war, your Eminence is now acting in such a
way as cannot fail happily to extricate them from the
consequences of their mistakes, and to frustrate the unjust
attitude of those nations who are ready to fall upon the
treasures of the new world.
We praise God, Monseigneur, and we pray with fervour
that He would preserve Your Eminence, not only for the
accomplishment of the great work which we are going to
undertake under your protection, but also that you may
see the great and happy effects throughout Europe as well
as in the three kingdoms of Britain in which your name will
be not less precious in all time to come than in France
itself, which has been enlarged so remarkably under your
ministry; and that the glory of your name will be raised to
the highest pitch by making justice flourish among your
neighbours. We have the Honour to be, with profound
veneration and perfect devotion, Monseigneur, Your
Eminence’s very humble and obedient servants.
The promises of assistance from the French Court brought by

Balhaldy, and the letter of acceptance by the lords of the Concert
constituted the treaty between France and the Scottish Jacobites
which formed the foundation of all subsequent schemes undertaken
in Scotland. Even in the end it was detachments of the Irish
regiments, whose use was originally suggested by Glenbucket,
together with a Scottish regiment raised later than this by Lord John
Drummond, that formed the meagre support that was actually sent
over from France in 1745.
Balhaldy returned to France almost immediately, and in the winter
of 1740-41, he went to England where he met the Jacobite leaders,
of whom he particularly mentions the Earls of Orrery and Barrymore,
Sir Watkin Williams Wynne, and Sir John Hinde Cotton. With them
he endeavoured to form a scheme of concert between the English
and the Scottish Jacobites, but without much success.[45]
It was not until after the signing of the letter to Murray taken
Fleury that Murray was taken into the confidence into the
of the Jacobite leaders, and it was at this time that confidence of
he first met Lord Lovat. This was also the occasion the Concert.
of his first meeting with Balhaldy; their relations at
this time were quite friendly; Balhaldy handed over to Murray the
negotiation of a delicate ecclesiastical matter with which he had
been entrusted by the Chevalier.[46]
Another early duty was to raise money for the Cause, but to
Murray’s mortification, he had to give up the scheme of a loan,
because all the sympathisers to whom he applied declined to
subscribe; not, they said, because they objected to giving their
money, but each and all refused to be the first to compromise himself
by heading the subscription list. At this time Murray was not
permitted to undertake any active propaganda for a rising, as the
associated leaders feared that by increasing the numbers in the
secret there would be too great danger of leakage. The Associators
preferred to keep such work in their own hands, and each of them
had a district assigned to him.
After Balhaldy’s departure the unfortunate Associators were kept
in a state of agonising suspense, for nothing was heard from France
until the end of 1742. In December of that year, Lord Traquair
received a letter from Balhaldy couched in vague terms, assuring
him that troops and all things necessary for a rising would be
embarked early in the spring. The scheme, he wrote, was to make a
landing near Aberdeen and another in Kintyre. The whole tone of the
letter was so confident that the Associators felt that a French
expedition might be expected almost immediately, and they were
profoundly conscious that Scotland was not ready. So alarmed were
the leaders at the possibility of a premature landing, and so
uncertain were they about the promises vaguely conveyed in
Balhaldy’s letter, that they determined to send Murray over to Paris
to find out what the actual French promises were, and how they were
to be performed; and moreover to warn the Government of King
Louis how matters stood in Scotland.
Murray set off in January 1743. On his way he visited the Duke of
Perth, then residing at York, making what friends he could among
the English Jacobites. When Murray got to London, he was informed
of Cardinal Fleury’s death,[47] which somewhat staggered him, but
he determined to go on to France to find out how matters stood.
On arriving in Paris, Murray met Balhaldy and
Sempill. Balhaldy was surprised and not
particularly glad to see him, but he treated him Murray’s visit to
courteously, and discussing affairs with Murray, he Paris, 1743.
patronisingly informed him that he had not been told everything.
Sempill was very polite. He told Murray that a scheme had been
prepared by Fleury, but that the Cardinal’s illness and death had
interrupted it.[48] Sempill also told him that luckily he had persuaded
the Cardinal to impart his schemes to Monsieur Amelot, the Minister
for Foreign Affairs. An interview with the Minister was obtained at

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Suman K. Chakravarti MultiCASE Inc., Beachwood, OH, United States

Pratim Kumar Chattaraj Department of Chemistry, Indian Institute of

Samrat Chatterjee Complex Analysis Group, Translational Health Science and

Ramana V. Davuluri Department of Preventive Medicine, Division of Health and

Tathagata Dey Centre for Interdisciplinary Research and Education, Kolkata,

Abhik Ghosh Indian Statistical Institute, Kolkata, West Bengal, India

Indira Ghosh School of Computational & Integrative Sciences, Jawaharlal Nehru

Giuseppina Gini Politecnico di Milano, DEIB, Piazza Leonardo da Vinci, Milano,

Lima Hazarika In silico Research Laboratory, Eminent Biosciences, Indore,

Guang Hu Department of Bioinformatics, Center for Systems Biology, School of

Chiakang Hung Politecnico di Milano, DEIB, Piazza Leonardo da Vinci, Milano,

Tajamul Hussain Biochemistry Department, College of Science, King Saud

Yanrong Ji Department of Preventive Medicine, Division of Health and

Isha Joshi In silico Research Laboratory, Eminent Biosciences, Indore, Madhya

Taushif Khan Immunology and Systems Biology Department, OPC-Sidra

Ravina Khandelwal In silico Research Laboratory, Eminent Biosciences, Indore,

Shivam Kumar Complex Analysis Group, Translational Health Science and

Min Li Department of Bioinformatics, Center for Systems Biology, School of

Jie Liao Department of Pathology, Northwestern University Feinberg School of

Claudiu N. Lungu Department of Chemistry, Faculty of Chemistry and

Subhabrata Majumdar AI Vulnerability Database, Seattle, WA, USA; Bias

Rama K. Mishra Department of Biochemistry and Molecular Genetics, Feinberg

Manju Mohan In silico Research Laboratory, Eminent Biosciences, Indore,

Anuraj Nayarisseri In silico Research Laboratory, Eminent Biosciences, Indore,

Ranita Pal Advanced Technology Development Centre, Indian Institute of

Aditi Pande In silico Research Laboratory, Eminent Biosciences, Indore, Madhya

Guillermo Restrepo Max Planck Institute for Mathematics in the Sciences,

Dipanka Tanu Sarmah Complex Analysis Group, Translational Health Science

Dwaipayan Sen Centre for Interdisciplinary Research and Education, Kolkata,

Sanjeev Kumar Singh Department of Bioinformatics, Computer Aided Drug

Chillamcherla Dhanalakshmi Srija In silico Research Laboratory, Eminent

Revathy Arya Suresh In silico Research Laboratory, Eminent Biosciences, Indore,

Muyun Tang Department of Bioinformatics, Center for Systems Biology, School

Garima Thakur In silico Research Laboratory, Eminent Biosciences, Indore,

Xin Tong Department of Pathology, Northwestern University Feinberg School of

Marjan Vracko Theory Department, Kemijski inštitut/National Institute of

Marjan Vračko National Institute of Chemistry, Hajdrihova 19, Ljubljana,

Ze Wang Department of Pharmaceutical Sciences, Zunyi Medical University at

DanDan Xu Department of Pathology, Northwestern University Feinberg School

Guang-Yu Yang Department of Pathology, Northwestern University Feinberg

For Information on all Elsevier publications

Publisher: Susan Dennis

Section 1 General section

2 Robustness concerns in high-dimensional data analyses and

2.4 Penalized M-estimation for robust high-dimensional analyses 44

3 Fairness, explainability, privacy, and robustness for

Section 2 Chemistry & chemoinformatics section

4.2 State and review 101

5 Big data and deep learning: extracting and revising

6 Retrosynthetic space modeled by big data descriptors 151