Journal of Molecular Graphics and Modelling 126 (2024) 108640

Contents lists available at ScienceDirect

Journal of Molecular Graphics and Modelling

journal homepage: www.elsevier.com/locate/jmgm

Finding structural requirements of structurally diverse α-glucosidase and

α-amylase inhibitors through validated and predictive 2D-QSAR and
3D-QSAR analyses
Soumya Mitra a, Subhadas Chatterjee a, Shobhan Bose a, Parthasarathi Panda a, Souvik Basak a,
Nilanjan Ghosh b, **, Subhash C. Mandal b, Saroj Singhmura a, Amit Kumar Halder a, *
a
Dr. B. C. Roy College of Pharmacy & Allied Health Sciences, Durgapur, 713206, India
b
Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India

A R T I C L E I N F O A B S T R A C T

Keywords: Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemic state. The α-glucosidase
T2DM and α-amylase are considered two major targets for the management of Type 2 DM due to their ability of
α-glucosidase metabolizing carbohydrates into simpler sugars. In the current study, cheminformatics analyses were performed
α-amylase
to develop validated and predictive models with a dataset of 187 α-glucosidase and α-amylase dual inhibitors.
Dual inhibitors
Separate linear, interpretable and statistically robust 2D-QSAR models were constructed with datasets containing
QSAR
the activities of α-glucosidase and α-amylase inhibitors with an aim to explain the crucial structural and phys­
icochemical attributes responsible for higher activity towards these targets. Consequently, some descriptors of
the models pointed out the importance of specific structural moieties responsible for the higher activities for
these targets and on the other hand, properties such as ionization potential and mass of the compounds as well as
number of hydrogen bond donors in molecules were found to be crucial in determining the binding potentials of
the dataset compounds. Statistically significant 3D-QSAR models were developed with both α-glucosidase and
α-amylase inhibition datapoints to estimate the importance of 3D electrostatic and steric fields for improved
potentials towards these two targets. Molecular docking performed with selected compounds with homology
model of α-glucosidase and X-ray crystal structure of α-amylase largely supported the interpretations obtained
from the cheminformatic analyses. The current investigation should serve as important guidelines for the design
of future α-glucosidase and α-amylase inhibitors. Besides, the current investigation is entirely performed by using
non-commercial open-access tools to ensure easy accessibility and reproducibility of the investigation which may
help researchers throughout the world to work more on drug design and discovery.

1. Introduction polyphagia, loss of weight and blurred vision. According to a report by

Diabetes mellitus (DM) is a chronic metabolic disorder characterized
by hyperglycemic state. Hyperglycemia results from insufficient insulin
secretion or loss of insulin activity or as a result of both. The disease
burden of diabetes mellitus is complicated by the generation of different
microvascular complications i.e., neuropathy, nephropathy, retinopathy
or macrovascular complications like peripheral and autonomic neu­
ropathy, increased incidence of atherosclerosis, peripheral and cere­
brovascular diseases [1,2]. Chronic hyperglycemia is considered to be
the primary characteristic trait of DM which includes polyuria,
the International Diabetes Federation, IDF Diabetes Atlas, 9th Edition
2019; approximately 436 million people are suffering from DM and the
number would reach up to 700 million by the end of 2045 [3]. Inter­
estingly enough, the prevalence of Type II Diabetes mellitus (T2DM) is
much higher in human beings which results from insulin resistance as
well as defects in insulin secretion. The role of oxidative stress in
aggravating pathological complications in T2DM is crucial, considering
the generation of reactive oxygen species (ROS) which inadvertently
causes damage to different organs and interrupts enzymatic pathways.
The highly volatile nature of the free radical causes oxidative stress to

* Corresponding author.
** Corresponding author.
E-mail addresses: nilanjanghosh.phamacy@jadavpuruniversity.in (N. Ghosh), amitcsir2011@gmail.com (A.K. Halder).

https://doi.org/10.1016/j.jmgm.2023.108640
Received 7 April 2023; Received in revised form 9 September 2023; Accepted 26 September 2023
Available online 27 September 2023
1093-3263/© 2023 Elsevier Inc. All rights reserved.
S. Mitra et al.
the cellular machinery by the formation of advanced glycation products
(AGEs) which play a key role in causing cellular damage. The excess
production of ROS through the polyol pathway leads to retrained anti­
oxidant enzymatic activity of the system resulting in enhanced oxidative
stress in hyperglycemic conditions [4,5]. The uphill management of
T2DM has brought a plethora of probable approaches ranging from
conventional lifestyle modifications to single-regime drug therapies.
However, recent developments have suggested the involvement of
multiple therapies to be more beneficial.
One of the most coveted approaches in combatting the relentless
damages caused by T2DM is through dual inhibition of α-glucosidase
and α-amylase enzymes. The α-glucosidase is one of the major
carbohydrate-digesting enzymes that is present in the brush borders of
the intestine and contributes in breaking down of complex oligosac­
charides into simple monosaccharides. The α-glucosidase inhibitors
delay the absorption of carbohydrates into the small intestines which
effectively allows pancreas to secrete enough insulin. These inhibitors
exert moderate antihyperglycemic action without interfering with the
insulin secretion directly, thus monotherapy is not recommended.
However, there are several adverse effects associated with α-glucosidase
inhibitors like acarbose; such as nausea, bloating and flatulence [6,7].
The α-amylase, a digestive endo-amylase secreted from the saliva and
pancreas, is crucial in metabolism of long chain polysaccharides into
simple carbohydrate like glucose. The enzyme catalyzes hydrolysis of
the α1→4 linkage of the polysaccharides into monosaccharides while
retaining the α-monomeric form of the same. The prompt hydrolysis of
the carbohydrates in simple glucose by α-amylase may also be consid­
ered to be one of the leading causes for T2DM which ultimately brings
forth the strategy of inhibiting the enzyme as a probable approach. In
this quest, triazinoindole, thiazolidin-4-one derivatives have been
extensively investigated for their possible α-amylase inhibitory potential
[8–10]. The findings suggested key structural scaffolds playing signifi­
cant role in offering inhibitory potential of the enzymes. This, coupled
with extensive literature survey from our group of researchers, have led
the notion for exploring scaffolds with dual inhibitory potential towards
the carbohydrate metabolizing enzymes; i.e. α-glucosidase and
α-amylase through ligand and structure based in silico studies and sub­
sequent design and development of the dual inhibitors [11].
Research investigations conducted by Khan et al. on design and
development of dual inhibitors of these enzymes reported a series of
compounds with potent inhibitory action [12–19]. These investigators
focused on diverse scaffolds such as triazole, triazine, indazole, indole,
dicyanoaniline, quinolinyl bearing thiadiazole-4-one, and
triazinoindole-thiazolidinone moieties for determining inhibitory action
against the enzymes. In their investigation, the synthesized compounds
were tested for their activity with maximum half inhibitory concentra­
tion (IC50) against both the enzymes and values ranged between 1.1 μM
and 66.77 μM for α-glucosidase while for α-amylase the values ranged
between 0.9 μM and 66.50 μM. Such wide range of biological activity for
focused library of diverse ligands require detailed in silico study to
identify structural features contributing to higher inhibitory action
against these enzymes.
In this current study, cheminformatic modelling approaches like 2D
and 3D quantitative structure activity relationship (2D-QSAR and 3D-
QSAR) have been performed to analyse the structural features in order
to enhance inhibitory potency against α-glucosidase and α-amylase.
From the enzyme kinetic studies by Khan et al., it was found that the
ligands can bind to the enzymes in competitive, non-competitive and
uncompetitive manner [12–19].
2. Materials and methods
2.1. Dataset collection and structure preparation
A total of 187 compounds of triazole, triazine, indazole, indole,
dicyanoaniline, quinolinyl bearing thiadiazole-4-one, and
2
Journal of Molecular Graphics and Modelling 126 (2024) 108640
triazinoindole-thiazolidinone classes were collected from the recent
studies conducted by Khan et al. [12–19]. The compounds were
renamed with numerical codes and suffixes as AT [12], BT [13], IZ [14],
TZ [15], DC [16], ID [17], TT [18] and TH [19]. The inhibitory activities
of these compounds were tested against α-glucosidase enzyme obtained
from brewer’s yeast Saccharomyces cerevisiae and while α-amylase was
obtained from human pancreas. The half maximum inhibitory concen­
tration (IC50 in μM) values of these compounds were calculated into
pIC50 (=-log10(IC50/106)) values and were subsequently used as the
response variables for 2D-QSAR and 3D-QSAR analyses. The structures,
in the form of SMILES, and biological responses of these ligands are
given in the supplementary material of this work. The 2D structures of
the compounds were drawn by using Chemsketch academic version and
they were changed to.sdf files by utilization of Discovery Studio Visu­
alization tools and were numbered subsequently. The structural opti­
mization of the compounds was carried out with Chemaxon standardizer
tool by using the following options: (a) explicit hydrogen atoms were
added, (b) compounds were aromatized, (c) cleaned 2D, (d) cleaned 3D,
(e) neutralized and (f) stripped of salts. The standardized structures were
further processed for 2D-QSAR and 3D-QSAR analyses [20].
2.2. 2D-QSAR analyses
2.2.1. Descriptor calculation
Descriptor calculation of the 187 compounds was carried out by
using alvaDesc v.2.0.4 (https://www.alvascience.com/alvadesc/) [21]
under OCHEM webserver [22]. Corina tool was utilized during
geometrical optimization of the structures for 3D descriptor calculation
[23]. The calculated descriptors of these ligands were then integrated
with respective pIC50 values of the compounds to develop the complete
dataset for 2D-QSAR model generation.
2.2.2. Dataset division and model development
Dataset division plays a key role towards generation of 2D QSAR
modelling. The dataset was split into a training set and a test set by using
k-means cluster analysis (kMCA) technique of Python based open-access
SFS-QSAR tool (https://github.com/ncordeirfcup/SFS-QSAR-tool) [24].
Dataset division was carried out by keeping 20% of the structures in test
set while k-MCA supplied a rational data-distribution strategy in which
the response variables as well as the independent variables are initially
clustered into eight groups and then the dataset was randomly divided
(random seed 42 in SFS-QSAR) into training set (80%) and test set
(20%). The 2D-QSAR models were developed by deploying two sets of
alvaDesc descriptors. First, only some selected interpretable descriptors
were used and these descriptors belong to the categories of constitu­
tional descriptors, functional group counts, 2D-atom pairs, drug-like
indices, ring descriptors, atom-centred fragments, pharmacophore de­
scriptors and molecular properties. Next, all alvaDesc descriptors were
applied to check whether inclusion of additional descriptors (relatively
less interpretable) is genuinely required for characterization of the
structural requirements of the dataset ligands. Two distinct feature se­
lection tactics were used for 2D-QSAR model development - (a)
sequential forward selection (SFS) and (b) genetic algorithm (GA). The
first SFS mediated model was developed by using python based open
access tool, SFS-QSAR (https://github.com/ncordeirfcup/SFS-QSAR-
tool) which administers ‘Feature Selector’ module of Mlxtend library
(http://rasbt.github.io/mlxtend/) [24]. Constant and near-constant
descriptors were eliminated by keeping the variance cut-off at 0.0001
while highly inter-correlated descriptors were eliminated by setting the
correlation cut-off at 0.99. Models were developed by using four scoring
functions from ‘Sequential Feature Selector’ module which included R2:
determination coefficient, NMAE: negative mean absolute error, NMPD:
negative mean Poisson deviance and NMGD: negative mean gamma
deviance. The models were generated with keeping 0-fold cross vali­
dation initially and 5-fold cross validation subsequently. GeneticAlgor­
ithm v.4.1_2 (accessed from https://dtclab.webs.com/software-tools)
S. Mitra et al.
[25], an open access tool was employed to establish GA-based models.
SFS uses a non-stochastic feature selection method which is distinctive
from GA which follows stochastic algorithms to develop randomized
models while implementing techniques like cross-over and mutations to
improve fitting of the independent variable with the response variables.
Descriptor pre-treatment was carried out for GA which is similar to
SFS-QSAR. Five descriptors were allowed for development of 2D-QSAR
model.
2.2.3. Statistical analyses of the models
The predictability of the eventual 2D-QSAR model was justified with
a number of well-established statistical parameters like determination of
R2, adjusted R2 (R2A), F-statistics, mean absolute error (MAE), and in­
ternal cross-validation parameter Q2LOO [26,27]. R2Pred, an external vali­
dation parameter was utilized to validate predictivity of the generated
models [28]. Parameters related to rm2 matrices like rm2LOO and Δrm2LOO
were also used for internal validation while external validation was
accomplished by rm2test and Δrm2test [29]. Inter-collinearity among the
descriptors of the best models were estimated from cross-correlation
matrices from the descriptors. Furthermore, variation inflation factor
(VIF) was calculated to estimate multi-collinearity of the generated
models (VIF = 1/1-R2i , where R2i is the determination coefficient (R2)
determined by regressing the ith descriptor on the other descriptors)
[30]. In addition to this, Y-randomization test was carried out 1000
times to generate 1000 randomized response variables. cR2p value was
calculated to confirm the fact that the final model was not created by
chance, which could be predicted by its higher value [31].
2.2.4. Applicability domain of the models
Applicability domain of the generated model was estimated by
Williams plot which is a plot generated between leverage values and
standardized coefficients. If leverage value of any data point exceeds the
hat value h* (h* = 3*p/n, where p is the number of model’s descriptors
+1 and n is the number of data-points in the training set), it is considered
to be structural outlier whereas, when standardized residual of the data-
point is > ±2.5, it is deemed to be a response outlier [32].
2.3. 3D-QSAR analyses
2.3.1. Alignment method
In this study, 3D-QSAR model development was carried out by atom-
based alignment or unsupervised rigid-body molecular alignment [33].
For atom-based alignment, ‘obminimize’ function from OpenBabel soft­
ware was employed which used steepest descent method for carrying out
the alignment. 100 conformations of the 3D structures of the ligands
were then generated and the alignment was accomplished by using
rdMolAlign.GetCrippenO3A program of RDKit. The python scripts for the
rigid-body based molecular alignment have been provided in https://gi
thub.com/ncordeirfcup/InsilicoModeling_RdRp.git.
2.3.2. Model development
An open-source software, Open3DQSAR, was used to perform 3D-
QSAR analyses [34]. This tool utilizes a carbon and volume-less posi­
tively (+1) charged probe to calculate steric and electrostatic field of the
provided ligands. Pre-treatment of the fields were carried out by keeping
smart region definition (SRD) cut-off level at 2.0 with removal of N-level
variables. The Open3DQSAR employs SRD for grouping variables based
on closeness of the variables in 3D space as well as two distinct algo­
rithms for variable selection are deployed, which are Fractional Facto­
rial Design-based variable SELection (FFD-SEL) and Uninformative
Variable Elimination-based Partial Least Square (UVE-PLS). Predictive
quality of the PLS models developed from the ligands was assessed by R2
with standardized errors of calibration (SDEC), F-test results,
leave-one-out Q2 (Q2LOO), leave-two-out Q2 (Q2LTO), leave-many-out Q2
(Q2LMO, with 5 groups and 20 runs) and R2Pred with associated
3
Journal of Molecular Graphics and Modelling 126 (2024) 108640
standardized errors of prediction (SDEP) values. To confirm whether the
generated model was distinct and not generated by serendipity, pro­
gressive scrambling operations were run for selected models with crit­
ical value: 0.80, type: LMO groups = 5, runs = 20 and scrambling = 20
as set criteria. ‘Fitted Q2 values’ in Open3DQSAR resulted as the
outcome of the scrambling test, which is denoted as Q2s in this study. Low
value of Q2s as compared to Q2LMO in this study justifies the robust nature
of the developed 3D-QSAR model. The contour maps were visualized
with isocontour values at PLS coefficients of +0.005 (green) and − 0.005
(yellow) for the steric field and the +0.003 (blue) and − 0.003 (red) for
electrostatic field. Matplotlib software has been used to generate all the
2D-QSAR and 3D-QSAR plots.
2.4. Structure based modelling
2.4.1. Homology modelling
The homology model of Saccharomyces cerevisiae α-glucosidase was
developed using SWISS-MODEL webserver [35]. The FASTA sequence
was obtained from Uniprot (access code P53341) [36]. The template
which was used for developing the homology model is Saccharomyces
cerevisiae isomaltase (PDB ID: 3AJ7) that possesses satisfactory sequence
similarity (72.4%) with α-glucosidase. Notably, in one of the previously
published report, Wang et al. also used the same FASTA sequence and
template for developing homology model of Saccharomyces cerevisiae
α-glucosidase [37]. After developing the model, its detailed structural
characterization was performed with the help of Molprobity webserver
(http://molprobity.biochem.duke.edu/index.php) [38].
2.4.2. Molecular docking
Molecular docking was performed with homology model of Saccha­
romyces cerevisiae α-glucosidase as well as human α-amylase, which was
retrieved from Protein Data Bank (PDB:3BAJ). For detection of cavity for
molecular docking, we explored CB-Dock2 that implements protein-
surface-curvature-based cavity detection technique (10.1093/nar/
gkac394). The molecular docking was performed with Autodock 4.2
[39]. For α-glucosidase, a grid was generated at X = 16.0, Y = − 14.0 and
Z = 15.0 with size of 40Å X 40Å X 40Å. On the other hand, the grid was
located at X = 8.3, Y = 15.1 and Z = 41.1 with the same extensions. The
docking steps involved preparation of protein that includes addition of
hydrogen atoms, Gasteiger charges and assigning the atoms with AD4
types. After preparing the PDBQT files (of proteins and ligands), Auto­
grid4 was run to generate the affinity maps for each atom type of the
ligands and subsequently, Autodock4 was run by setting genetic algo­
rithm as ‘Search parameter’ and Lamarckian GA (4.2) as output
parameter file. Default settings were used for the remaining docking
parameters. The docked poses were analysed using Discovery Studio
Visualizer tool.
3. Results and discussions
3.1. 2D-QSAR models: α-glucosidase inhibitors
As described earlier in the study, the 2D-QSAR model was developed
by using all alvaDesc descriptors by deploying two feature selection
techniques i.e., sequential forward selection (SFS) and genetic algorithm
(GA). The generated models were compared for best statistical quality it
was found that 2D-QSAR model generated with SFS by R2 scoring and 5-
fold cross-validation had slightly better statistical quality than those
generated by GA-MLR. The findings have been presented in Table 1.
From Table 1, it can be deduced that as compared to the models
developed with selected interpretable descriptors, significant improve­
ment is noticed in the statistical quality of the model when all de­
scriptors are used. When all descriptors are employed, SFS based feature
selection strategy coupled with R2 scoring function and 5-fold cross-
validation produced the model with maximum overall predictivity.
Moreover, we observed that this model was indeed generated with five
S. Mitra et al. Journal of Molecular Graphics and Modelling 126 (2024) 108640

Table 1

= 0.841,
2D-QSAR analyses of α-glucosidase inhibitors with some interpretable and all
descriptors (the most significant model is marked in bold).
Methoda Scoreb Foldc Interpretable descriptorsd All descriptorse

Ntraining = 147, R2 = 0.899, R2Adj = 0.896, F(F(5,141)) = 251.47, Q2LOO = 0.886, MAE = 0.133, r2LOO
m
Q2LOO R2Pred Q2LOO R2Pred

SFS R2 0 0.812 0.765 0.879 0.81

NMAE 0 0.83 0.765 0.885 0.837
NMPD 0 0.812 0.765 0.87 0.845
NMGD 0 0.812 0.765 0.87 0.845
R2 5 0.808 0.821 0.886 0.859
NMAE 5 0.79 0.764 0.876 0.786
NMPD 5 0.805 0.777 0.886 0.859
NMGD 5 0.805 0.777 0.886 0.859

m = 0.075
GA NA NA 0.835 0.806 0.872 0.866

a: Feature selection methods, SFS: sequential forward selection, GA: Genetic

m = 0.823, Δrtest
algorithm, b: Scoring functions used in SFS, check the main text for full names, c:

2
cross-validation methods used for SFS based feature selection, 0: No cross-
validation, 5: 5-fold cross validation, d: Only selected categories of descriptors
with high mechanistic interpretability are used (see the main text), e: all alva­

= 0.076, Ntest = 40, R2Pred = 0.859, r2test

Desc descriptors were employed for model development.

descriptors with significantly high interpretability. Therefore, this

model is therefore discussed in the current work. The equation and the
statistical results of the SFS-MLR model is presented in Table 2.
The 2D-QSAR model explains 89.6% and predicts 88.6% variances of
the response variable with five descriptors. The models depicted satis­
factory external predictivity with R2Pred of 0.859, r2test 2
m of 0.823 and Δrtest

Statistical resultsa
m
of 0.075. The maximum intercollinearity of the model was found as
0.495 indicating that the descriptors of the models are independent from
each other. We performed Y-randomization test with the model with

Δr2LOO
1000 run to determine the cR2p value as 0.881 suggesting the model is

m
itself unique and was not developed by chance. After confirming sta­
tistical robustness, we determined the applicability domain of the model

Ntraining: Number of data-points present in the training set; Ntest: Number of data-points present in the test set.
pIC50_glc = 1.055( ± 0.155)*TDB03i + 0.46( ± 0.051)*C-043 + 0.581( ± 0.02)*SaasN + 0.685( ± 0.127)
with the help of Williams plot, which is a plot of leverage vs standardized
residual. Three training set compounds and one test set compound were
found as structural outliers. Removal of the outlier from the test set,
improves the external predictivity of the model with R2Pred of 0.867. The
observed vs predicted activity plot and Williams plot of the model are
presented in Fig. S1 of supplementary materials. The relative signifi­
Summary of the SFS-MLR model developed with all descriptors for α-glucosidase inhibitors.

cance of each descriptor of 2D-QSAR model presented in Table 2 is

shown in Fig. 1.
As deduced from Table 2 and Fig. 1, the most significant descriptor of
the model was TDB03i, which belongs to 3D type of descriptors which
indicates 3D topological distance-based descriptors - lag 3 weighted by
*B09[S–Cl] + 0.529( ± 0.064)*CATS3D_07_DD + 0.44( ± 0.594)

ionization potential. This descriptor indicates that specific 3D geometry

and topology of the compounds play crucial role in determining the
biological activity of the compounds against α-glucosidase enzyme. At
the same time, the ionizability of these compounds significantly
contribute to the variations in the biological activity. The next most
significant descriptor is found to be B09[S–Cl], a 2-D atom pair
descriptor, which simply signifies the presence or absence of sulphur
and chlorine at topological distance of 9 [40]. Positive correlation of the
descriptor in the equation indicates that compounds with higher value of
this descriptor is found in some higher active compounds, as depicted in
Fig. 2. For instance, higher active compounds 6TT and 3TH possess atom
pairs S and Cl at topological distance of 9 whereas lower active com­
pounds 19DC and 12TZ do not possess the said atom pair, owing to
which, they may have lower inhibitory potential.
Equation (1)

The next most significant descriptor of the model is SaasN, an atom-

type E-state indices descriptor, which depicts the sum of total number of
nitrogen atom connected with one single bond along with two aromatic
bonds [41]. Being positively correlated with the response variable, the
greater value of this descriptor clearly favours the higher activity against
descriptors

α-glucosidase. The phenomenon is represented in Fig. 3 which shows

Descriptors

higher active compounds 9IZ and 15IZ with nitrogen containing aro­
Table 2

matic scaffolds (i.e., pyrazole moiety). On the other hand, the pair of
All

4
S. Mitra et al. Journal of Molecular Graphics and Modelling 126 (2024) 108640

Fig. 1. Relative significance of individual descriptor in the 2D-QSAR model for α-glucosidase inhibitors.

Fig. 2. Importance of the B09[S–Cl] descriptor with respect to selected dataset compounds.

compounds 5ID and 14TZ do not contain the said scaffolds, resulting in
potentially lower inhibitory activity.
Chemically advanced template search (CATS) descriptors have been
particularly useful in determining structural requirements in compounds
with greater biological activity. The fourth most significant descriptor
from the dataset was found to be CATS3D_07_DD, a 3D-pharmacophore
descriptor that signifies topological distance of 7 between two hydrogen
bond donor features [42]. Having positive correlation with the pIC50,
higher values of these descriptors were found in compounds with greater
inhibitory potentials. Indeed, some highly active compounds of the
datasets were found to possess higher CATS3D_07_DD values (i.e., 1), as
exemplified in Fig. 4, whereas less and even moderately active
compounds lacked such structural features (i.e., CATS3D_07_DD = 0).
The last descriptor, C-043, is an atom centred fragment descriptor
which is easily interpreted. The positive correlation of the descriptor
depicts the presence of the fragments with higher biological activity as
seen in Fig. 5. The C-043 atom centred fragment descriptor, represented
by X–CR..X which depicts X as any electronegative atom (halogens or S,
O, N etc.) while R can be any group linked through C [43]. For example,
compounds 19TH and 10TT have atom centre C attached with electro­
negative atom while lower active compounds like 17ID and 4DC do not
possess the aforementioned atom centre.

5
S. Mitra et al.
Fig. 3. Significance of the SaasN descriptor with respect to selected dataset compounds.
Fig. 4. Significance of the CATS3D_07_DD descriptor with respect to selected dataset compounds.
3.2. 2D-QSAR models: α-amylase inhibitors
A similar approach was taken to develop the 2-D QSAR model of the
α-amylase inhibitors. All AlvaDesc descriptors were used for generation
of the 2D-QSAR model by deploying SFS-QSAR tool and GeneticAlgor­
ithm v.4.1_2. Findings from these two different types of 2D-QSAR model
generation are given in Table 3, which suggests that GA based 2D-QSAR
model was better perceived in terms of statistical significance.
From the developed models, it could be seen that the statistical
quality of model produced by GA with all alvaDesc descriptors possesses
the most satisfactory statistical predictivity. This 2D-QSAR model with
five descriptors is presented below in Table 4 and the plot between
observed and predicted values along with Williams plot have been
provided in Fig. S2 of Supplementary material.
Equation in Table 4 demonstrates the 2D-QSAR models of α-amylase
inhibitors provided satisfactory statistical quality that is similar to the
model developed with α-glucosidase inhibitors. For example, the model
afforded high internal predictivity as suggested by Q2LOO of 0.866. At the
same time, high value of r2LOO
m (=0.814) and low values of MAE (=0.14)
as well as Δr2LOO
m (0.091) further indicate the same. As far as the external
predictivity is concerned, high R2Pred of 0.875 indicates that the model
achieved satisfactory predictivity, whereas the parameters determined
from r2m metrics also approved that. Maximum inter-collinearity of the
model was found to be 0.565 which suggested that the descriptors are
6
Journal of Molecular Graphics and Modelling 126 (2024) 108640
independent of each other. The Y-randomization test of the model with
1000 runs was performed to establish whether the model was developed
by luck, but the cR2p value of 0.862 suggests its unique nature. It is to be
observed that for both α-glucosidase and α-amylase 2D-QSAR model
development, 147 data points were considered for training set (Ntraining),
while 40 data points were considered for test set (Ntest). Afterwards,
Williams plot was deployed to determine the applicability domain of the
developed model and only one training set compound was found as
structural outlier in the model.
As shown in Fig. 6, the most significant descriptor of Equation 2was
found to be RDF010m, which is a radial distribution function type
descriptor used for defining 3D molecular structure with atomic
numbers weighted by mass [40]. Negative correlation of this descriptor
with the dataset compounds imply that lower values can be associated
with compounds having greater α-amylase inhibitory potency. The
presence of this descriptor clearly indicates that 3D-geometry weighed
by atomic mass should play significant roles in determining the bio­
logical activity. The second most significant descriptor from Equation 2
was found to be CATS3D_07_DD that has been explained previously. This
3D-pharmacophore descriptor, being positively correlated to the dataset
compounds imply that the 3D geometry of the compounds plays pivotal
role in determining inhibitory action of the compounds. Interestingly,
the next significant descriptor of the model is SaasN, which was also
found in the most predictive 2D-QSAR model of α-glucosidase [41]. This
S. Mitra et al. Journal of Molecular Graphics and Modelling 126 (2024) 108640

Fig. 5. Significance of the C-043 descriptor with respect to selected dataset compounds.

distance of 10 while compounds with relatively lower activity i.e. 16DC

Table 3
and 14TZ do not possess the atom pair as represented in Fig. 8. This
2D-QSAR analyses of α-amylase inhibitors with some interpretable and all de­
implies that having only S in the structure may not be enough to impart
scriptors (the most significant model is marked in bold).
greater biological activity. The last descriptor with the lowest signifi­
Methoda Scoreb Foldc Interpretable descriptorsd All descriptorse
cance from Equation 2is HVcpx, graph vertex complexity vertex, which
Q2LOO R2Pred Q2LOO R2Pred is an information indices descriptor calculated on the basis of contents of
SFS R2 0 0.756 0.704 0.881 0.775 molecules, based on the calculation of equivalence classes from the
NMAE 0 0.823 0.783 0.877 0.838 molecular graph [44].
NMPD 0 0.807 0.766 0.872 0.831
NMGD 0 0.800 0.780 0.872 0.831
R2 5 0.801 0.803 0.880 0.854 3.3. 3D-QSAR analyses
NMAE 5 0.777 0.768 0.875 0.838
NMPD 5 0.801 0.780 0.878 0.795
With rigid body alignment technique, the structures of both
NMGD 5 0.795 0.786 0.878 0.795
GA NA NA 0.815 0.808 0.866 0.875
α-glucosidase inhibitors and α-amylase inhibitors of the current dataset
were aligned. The aligned structures were thereafter used in developing
a: Feature selection methods, SFS: sequential forward selection, GA: Genetic 3D-QSAR models with Open3DQSAR tool. Two different feature selec­
algorithm, b: Scoring functions used in SFS, check the main text for full names, c:
tion techniques, such as FFD-SEL and UVE-PLS were utilized to develop
cross-validation methods used for SFS based feature selection, 0: No cross-
3D-QSAR models, the results of which are presented in Table 5.
validation, 5: 5-fold cross validation, d: Only selected categories of descriptors
with high mechanistic interpretability are used (see the main text), e: all alva­ The UVE-PLS technique provided the models with higher statistical
Desc descriptors were employed for model development. qualities for both α-glucosidase and α-amylase datasets. Satisfactory
internal predictivity of α-glucosidase 3D-QSAR model is perceived from
electrotopological state indices type descriptor shows positive correla­ Q2LOO of 0.773, Q2LTO of 0.773 and Q2LMO of 0.763. With 37 test set mol­
tion with the dataset compounds, revealing the presence of N atoms ecules, this model yielded R2Pred of 0.732. The model was subjected to
connected with one single along with two aromatic bonds being more randomization test that provided Q2s of 0.656 indicating that the model
significant towards α-amylase inhibitory action. The dataset compounds was not developed by luck. The contour maps of this model are pre­
like 8IZ and 12IZ have greater value corresponding to SaasN descriptor sented below in Fig. 9.
while less active compounds like 8ID and 7TZ show low value of the said From the 3D-QSAR model of α-glucosidase, it was found that the
descriptor as can be depicted from Fig. 7. Noticeably, these two de­ contribution of steric and electrostatic fields was 0.497 and 0.503,
scriptors are also seen in 2D-QSAR analysis for α-glucosidase inhibitors respectively. It is evident from the model that both fields have
implying that there is significant correlation existing between the contributed almost equally towards the model development. When the
α-amylase and α-glucosidase inhibition of the dataset compounds. most potent α-glucosidase inhibitor 19TH is compared with the least
The fourth most significant descriptor from Equation 2 has been potent compound 17DC, it was observed that 19TH could escape the
identified as positively correlated descriptor B10[C–S]. This 2D-atom steric unfavourable contour due to conformational flexibility that is less
pair descriptor depicts the presence or absence of C and S at topologi­ for 17DC. The methyl group on the thiazole ring in 19TH lies in very
cal distance of 09 [40]. Compounds with higher α-amylase inhibitory close proximity to the steric favourable contour maps, while the absence
potential i.e., 17TH and 11IZ contain S and C atoms at topological of bulky group/s in the steric unfavourable region also contributes to the
higher inhibitory potential of the ligand. A stark contrast may be seen in

7
S. Mitra et al. Journal of Molecular Graphics and Modelling 126 (2024) 108640

case of the least active compound 17DC which is deprived of bulky

moieties in the steric favourable region and cyano groups can be found

= 0.814,
lying closely to steric unfavourable contour maps. Additionally, furan
moiety in 17DC can been seen inserted in the steric unfavourable con­

Ntraining = 147, R2 = 0.879, R2Adj = 0.875, F(5,147) = 205.71, Q2LOO = 0.866, MAE = 0.14, r2LOO
tour region which may result in low inhibitory potential of the ligand.

m
Upon studying the electrostatic contour maps, it has been found that
electron deficient thiazole moiety and the hydrogen present in hydroxyl
(OH) groups of the best active compound 19TH are nearer to electro­
positive contour maps while the electron-rich acetohydrazide skeleton
lies in very close proximity of the electronegative favourable contour
map contributing to the higher activity of the dataset ligand. Conse­

m = 0.095.
quently, the lowest active compound 17DC contains electron deficient
aromatic ring at electropositive contour map, resulting in low inhibitory
potential of the compound.
m = 0.832, Δrtest
2

In case of α-amylase inhibitors, satisfactory internal predictivity of

the 3D-QSAR model has been achieved from Q2LOO of 0.779, Q2LTO of
0.779 and Q2LMO of 0.769. For 37 test set molecules, R2Pred of the model
was calculated to be 0.738. The model was further subjected to
= 0.091, Ntest = 40, R2Pred = 0.875, r2test

randomization test that provided Q2s of 0.651 implying that the model
development was not a fluke. The contour maps of this model are pre­
sented below in Fig. 10.
For 3D-QSAR model of α-amylase, 0.53 and 0.47 were found to be
the contributions of the steric and electrostatic fields, respectively. From
this model, it can be comprehended that contribution of both the fields
are equally important for the model generation though steric contribu­
Statistical resultsa

tion slightly higher. Upon observing the contour maps of the most potent
α-amylase inhibitor 17TH, it can be observed that the bulky 4-methyl
thiazole moiety is inserted into the steric favourable region of the con­
Δr2LOO

tour map while the rest of the remaining bulky structure escapes the
m

steric unfavourable region. This might be considered as one of the major

reasons behind the higher activity of the compound. On the contrary, the
pIC50_aml=0.442( ± 0.045)*B10[C–S] + 0.551( ± 0.068)*CATS3D_07_DD + 0.444( ± 0.023)*SaasN + (− 0.93)(

lowest active ligand 26DC with α-amylase inhibitory potential contains

Ntraining: Number of data-points present in the training set; Ntest: Number of data-points present in the test set.

no bulky moieties in the steric favourable contour region. Additionally,

bulky aromatic moieties can be seen inserted into the steric unfav­
ourable region of the contour maps which contributes to its low activity.
The electrostatic contour maps also reveal significant contributions
regarding the α-amylase inhibitory potential of the dataset ligands. As
seen in Fig. 10, electron-deficient thiazole moiety and electron-deficient
groups of the highest active ligand 17TH are close to electropositive
Summary of the GA-MLR models developed with all descriptors for α-amylase inhibitors.

contour map while the electron rich hydrazide skeleton and hydroxyl
(OH) group are almost embedded in the electronegative contour region.
A contrasting structural attribute can be observed in the lowest active
compound 26DC which lacks the favourable electrostatic characteristics
± 0.091)*RDF010 m + 0.217( ± 0.079)*HVcpx + 4.559( ± 0.238)

to induce higher inhibitory potential.

3.4. Molecular docking analyses

No crystallographic structure of Saccharomyces cerevisiae of

α-glucosidase enzyme is available yet. The homology model of Saccha­
romyces cerevisiae α-glucosidase was developed with GMQE (Global
Model Quality Estimate) of 0.95 and QMEANDisCo of 0.91 indicating
that the model was produced with satisfactory quality. Furthermore,
when assessed with Molprobity, a score of 1.11 was obtained that clearly
indicates that model fulfils most of the criteria for being a homology
model with good structural qualities. In spite of having a slightly higher
but acceptable clash score of 1.39, favoured region of Ramachandran
plot was found as 96.36%. The Ramachandran plot of the homology
model developed for Saccharomyces cerevisiae α-glucosidase is presented
Equation (2)

in Fig. S3 of supplementary materials.

Two dataset compounds (17TH and 7DC) with significant variations
in their biological activity against these enzymes were used for docking
analyses with these two enzymes and interactions of their best docked
descriptors

poses are shown in Fig. 11.

Descriptors

The higher active compound 17TH depicted binding energies of

Table 4

− 9.62 kcal/mol and − 9.78 kcal/mol with α-glucosidase and α-amylase

All

enzymes, respectively. On the other hand, for the lower active

a

8
S. Mitra et al.
Fig. 6. Relative importance of each descriptor in the 2D-QSAR model for α-amylase inhibitors.
Fig. 7. Significance of the SaasN descriptor with respect to selected dataset compounds.
compound 7DC, these values are − 6.91 kcal/mol and − 7.42 kcal/mol,
respectively. Therefore, the docking methodology at least discriminates
the binding behaviours of these two dataset compounds. However, the
main objective of performing the docking is to compare the ligand-
receptor interactions with the mechanistic interpretations obtained
from 2D- and 3D-QSAR methodologies. The significance of the 4-meth­
ylthiazole scaffold and hydroxyl groups of phenyl moiety was obtained
from 2D-QSAR analyses and from the docking interactions these in­
teractions are clearly found to be important. The hydroxyl groups of
17TH formed hydrogen bond interactions with the binding site amino
acids while the pi-alkyl interactions (that depends both on the hydro­
phobic and electronic environment of the aromatic ring) were observed
between 4-methylthiazole scaffold and surrounding amino acids.
Noticeably, 3D-QSAR modelling hinted that both steric and electrostatic
interactions of 4-methylthiazole scaffold (of 19TH, which is close to
17TH both structurally and biologically) are important for higher ac­
tivity against these enzymes. Similarly, the electronic contributions of
9
Journal of Molecular Graphics and Modelling 126 (2024) 108640
the hydroxyl groups of phenyl ring were clearly depicted in 3D-QSAR
models developed with α-glucosidase and α-amylase enzymes. The
involvement of the acetohydrazide moiety of 17TH for polar in­
teractions were also insinuated by the 3D-QSAR models because of the
closeness of electrostatic contours near this moiety. As per the 3D-QSAR
models, unfavourable steric interactions played a significant role in
lowering the activity of 7DC whereas molecular docking suggested that
a comparatively lower number of interactions at the binding site may be
responsible for relatively low binding energy of such compounds against
these enzymes. The central aromatic moiety of 7DC failed to show sig­
nificant interactions with the receptors whereas the interactions of
amino as well as cyano groups varied considerably. Among three aro­
matic moieties, only pyridine moiety interacted strongly with sur­
rounding amino acids.
S. Mitra et al. Journal of Molecular Graphics and Modelling 126 (2024) 108640

Fig. 8. Significance of the B10[C–S] descriptor with respect to selected dataset compounds.

with small number of data-points. Investigations carried out with rela­

Table 5 tively large number of data-points were based on the classification an­
Statistical results of 3D-QSAR analyses of α-glucosidase and α-amylase
alyses. The current study describes the regression-based validated and
inhibitors.
predictive 2D- and 3D-QSAR models in order to understand the struc­
Parameter* α-glucosidase α-amylase tural requirements of 187 compounds reported as α-glucosidase and
FFD-SEL UVE-PLS FFD-SEL UVE-PLS α-amylase inhibitors by the same group of research investigators. A few
PC 2 2 2 2 interesting facts encouraged us to perform receptor-independent and
NTraining 150 150 150 150 ligand-based cheminformatic analyses. First, no X-ray crystal structure
F-test 318.36 396.50 285.51 411.67 of α-glucosidase is available that leaves better scopes for ligand-based
R2/SDEC 0.814/0.219 0.844/0.201 0.795/0.231 0.848/0.198 methodologies. Second, the inhibitory potencies against these two en­
Q2LOO/SDEP 0.730/0.264 0.773/0.242 0.709/0.275 0.779/0.239
Q2LTO/SDEP 0.730/0.264 0.773/0.242 0.709/0.275 0.779/0.239
zymes are highly correlated and each dataset compound may thus in fact
Q2LMO/SDEP 0.718/0.269 0.763/0.247 0.699/0.280 0.769/0.245 be considered as dual inhibitors of α-glucosidase and α-amylase.
NTest 37 37 37 37 Nevertheless, separate cheminformatic models were developed for these
R2Pred/SDEP 0.705/0.265 0.732/0.252 0.693/0.280 0.738/0.259 activities and this is why, the models developed here may be considered
Q2s ND 0.545 ND 0.651
significant for both these activities. The 2D-QSAR models were devel­
oped with significantly reliable statistical qualities with a smaller
3.5. Design of new compounds number of descriptors and at the same time, these specifically pointed
out the structural attributes responsible for higher inhibitory potentials
The current work mainly focuses on the development of linear pre­ against these enzymes. It was found that apart from specific 2D- and
dictive models to understand structural requirements of diverse sets of 3D-topologies, the physicochemical properties such as mass and ioni­
ligands for their activity against α-amylase and α-glucosidase activity. zation potential play crucial role in determining the activity of the
This is why we performed feature selection techniques in 2D-QSAR in compounds. Considerably high statistical predictions were obtained
order to collect the most significant descriptors to describe structural from the 3D-QSAR models as well and the contour maps generated in the
features responsible for higher inhibition. Nevertheless, these models models justified the variations observed in the activities among the
may be utilized to design new molecules. In this work, we demonstrate α-glucosidase and α-amylase inhibitors. Moreover, we found consis­
one such example NC1 (Fig. 12). It was observed that the most potent tencies among the interpretations of 2D- and 3D-QSAR models. For
α-glucosidase inhibitor of the dataset had low value of SaasN descriptor example, the importance of hydroxyl groups and acetohydrazide moi­
whereas it had CATS_07_DD value of 1. We designed a new compound eties as well as topological distance between two aromatic moieties in
which increased the value of SaasN at the expense of CATS_07_DD since higher active compounds (19TH, 17TH and 7TH) are shown by both the
the former had slightly higher significance than the latter. As expected, 2D-QSAR and 3D-QSAR models. In the α-glucosidase 2D-QSAR model,
the predicted pIC50 value against α-glucosidase improved and at the the descriptor weighed by ionization potential (i.e., TDB03i) and in the
same time, the designed molecule NC1 remained inside the applicability α-amylase 2D-QSAR model, the descriptor weighted by atomic mass (i.
domain of the model. When this compound was docked with α-gluco­ e., RDF010m) remained the most crucial descriptors. Such information
sidase, a binding energy of − 8.74 kcal/mol was obtained. is reflected by the fact that in their 3D-QSAR models, steric and elec­
trostatic interactions were found to be equally important in determining
the biological activity. More interestingly, 3D-QSAR models highlighted
4. Conclusion
importance of interactions with unfavourable steric contours with bulky
atoms for lowering the activity and this information is consistent with
Previously, a number of investigations described cheminformatics
the fact that RDF010m appeared to have a negative influence on
analyses of α -glucosidase and α-amylase inhibitors [45–50]. These in­
inhibitory potency against α-amylase. Additionally, this work reports
vestigations were either reported with only one of these enzymes and/or

10
S. Mitra et al. Journal of Molecular Graphics and Modelling 126 (2024) 108640

Fig. 9. Contour maps obtained from the best 3D-QSAR model for α-glucosidase data (Green: Steric favourable, Yellow: Steric unfavourable, Blue: Electropositive
favourable; Red: Electronegative favourable). (A) Steric maps of the best active compound 19TH, (B) Steric maps of the least active compound 17DC, (C) Electrostatic
maps of the best active compound 19TH and (D) Electrostatic maps of the least active compound 17DC. (For interpretation of the references to colour in this figure
legend, the reader is referred to the Web version of this article.)

Fig. 10. Contour maps obtained from the best 3D-QSAR model for α-amylase data (Green: Steric favourable, Yellow: Steric unfavourable, Blue: Electropositive
favourable; Red: Electronegative favourable). (A) Steric maps of the best active compound 17TH, (B) Steric maps of the least active compound 26DC, (C) Electrostatic
maps of the best active compound 17TH and (D) Electrostatic maps of the least active compound 26DC. (For interpretation of the references to colour in this figure
legend, the reader is referred to the Web version of this article.)

molecular docking with selected number of ligands and ligand receptor
interactions complied well with QSAR interpretations. Even though this
work emphasized mainly on the structural characterization, as it is
shown in the design of a new compound NC1, this investigation should
serve as important guidelines for the design of future α-glucosidase and
α-amylase inhibitors. More importantly, the current work is entirely
performed by using non-commercial open-access tools to ensure easy
accessibility and reproducibility of the investigation which may help
researchers throughout the world to work more on drug design and
discovery.

11
S. Mitra et al. Journal of Molecular Graphics and Modelling 126 (2024) 108640

Fig. 11. Binding interactions between α-glucosidase enzyme and dataset compounds 17TH (A) and 7DC (B) and between α-amylase and dataset compounds 17TH
(C) and 7DC (D).

Declaration of competing interest

The authors declare that they have no known competing financial

interests or personal relationships that could have appeared to influence
the work reported in this paper.

Data availability

I have shared the data at the Attach File step of submission

Acknowledgement

The authors are thankful to Dr. B. C. Roy College of Pharmacy and

Allied Health Sciences for providing infrastructures and support for the
current work.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.

org/10.1016/j.jmgm.2023.108640.

References

Fig. 12. Structure of the newly designed compound NC1.
[1] J. de F. Maraschin, Classification of diabetes, Adv. Exp. Med. Biol. 771 (2012)
12–19.
[2] B. Fletcher, M. Gulanick, C. Lamendola, Risk factors for type 2 diabetes mellitus,
J. Cardiovasc. Nurs. 16 (2002) 17–23.
[3] American Diabetes Association, 2. Classification and diagnosis of diabetes:
standards of medical care in diabetes-2020, Diabetes Care 43 (Suppl 1) (2020)
S14–S31, https://doi.org/10.2337/dc20-S002.

12
S. Mitra et al.
[4] F. Giacco, M. Brownlee, Oxidative stress and diabetic complications, Circ. Res. 107
(2010) 1058–1070.
[5] M.A. Darenskaya, L.I. Kolesnikova, S.I. Kolesnikov, Oxidative stress: pathogenetic
role in diabetes mellitus and its complications and therapeutic approaches to
correction, Bull. Exp. Biol. Med. 171 (2021) 179–189.
[6] U. Ghani, Re-exploring promising α-glucosidase inhibitors for potential
development into oral anti-diabetic drugs: finding needle in the haystack, Eur. J.
Med. Chem. 103 (2015) 133–162.
[7] J.J. DiNicolantonio, J. Bhutani, J.H. O’Keefe, Acarbose: safe and effective for
lowering postprandial hyperglycaemia and improving cardiovascular outcomes,
Open heart 2 (2015), e000327.
[8] N. Kaur, V. Kumar, S.K. Nayak, P. Wadhwa, P. Kaur, S.K. Sahu, Alpha-amylase as
molecular target for treatment of diabetes mellitus: a comprehensive review,
Chem. Biol. Drug Des. 98 (2021) 539–560, https://doi.org/10.1111/cbdd.13909.
[9] S. Chahal, J. Punia, P. Rani, R. Singh, P.K. Mayank, R. Kataria, G. Joshi, J. Sindhu,
Development of thiazole-appended novel hydrazones as a new class of α-amylase
inhibitors with anticancer assets: an in silico and in vitro approach, RSC med. 14
(2023) 757–781.
[10] K. Date, A. Satoh, K. Iida, H. Ogawa, Pancreatic α-amylase controls glucose
assimilation by duodenal retrieval through N-Glycan-specific binding, endocytosis,
and degradation, J. Biol. Chem. 290 (2015) 17439–17450.
[11] R. Singh, P. Kumar, J. Sindhu, M. Devi, A. Kumar, S. Lal, D. Singh, Parsing
structural fragments of thiazolidin-4-one based α-amylase inhibitors: a combined
approach employing in vitro colorimetric screening and GA-MLR based QSAR
modelling supported by molecular docking, molecular dynamics simulation and
ADMET studies, Comput. Biol. Med. 157 (2023), 106776.
[12] E. Oyeye, Kanwal, K.M. Khan, S. Chigurupati, A. Wadood, A.U. Rehman,
S. Perveen, M.K. Maharajan, S. Shamim, S. Hameed, S.A. Aboaba, M. Taha,
Syntheses, in vitro α-amylase and α-glucosidase dual inhibitory activities of 4-
amino-1,2,4-triazole derivatives their molecular docking and kinetic studies,
Bioorg. Med. Chem. 28 (2020), 115467.
[13] S. Hameed, Kanwal, F. Seraj, R. Rafique, S. Chigurupati, A. Wadood, A.U. Rehman,
V. Venugopal, U. Salar, M. Taha, K.M. Khan, Synthesis of benzotriazoles
derivatives and their dual potential as α-amylase and α-glucosidase inhibitors in
vitro: structure-activity relationship, molecular docking, and kinetic studies, Eur. J.
Med. Chem. 183 (2019), 111677, 2019.
[14] R. Rafique, K.M. Khan, Kanwal Arshia, S. Chigurupati, A. Wadood, A.U. Rehman,
A. Karunanidhi, S. Hameed, M. Taha, M. Al-Rashida, Synthesis of new indazole
based dual inhibitors of α-glucosidase and α-amylase enzymes, their in vitro, in
silico and kinetics studies, Bioorg. Chem. 94 (2020), 103195.
[15] S. Shamim, K.M. Khan, N. Ullah, S. Chigurupati, A. Wadood, A.U. Rehman, M. Ali,
U. Salar, A. Alhowail, M. Taha, S. Perveen, Synthesis and screening of (E)-3-(2-
benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazine analogs as novel dual
inhibitors of α-amylase and α-glucosidase, Bioorg. Chem. 101 (2020), 103979.
[16] S. Faiza, A. Kanwal, K.M. Khan, S. Chigurupati, Y. Andriani, M. Solangi, S. Hameed,
A.A. Monem, A. Hafez, F. Begum, M.A. Lodhi, M. Taha, F. Rahim, T.S.
T. Muhammad, S. Perveen, Dicyanoanilines as potential and dual inhibitors of
α-amylase and α-glucosidase enzymes: synthesis, characterization, in vitro, in
silico, and kinetics studies, Arab, J. Chem. 15 (2022), 103651.
[17] A.N. Kawde, M. Taha, R.S. Alansari, N.B. Almandil, E.H. Anouar, N. Uddin,
F. Rahim, S. Chigurupati, M. Nawaz, S. Hayat, M. Ibrahim, P.K. Elakurthy,
V. Vijayan, M. Morsy, H. Ibrahim, N. Baig, K.M. Khan, Exploring efficacy of indole-
based dual inhibitors for α-glucosidase and α-amylase enzymes: in silico,
biochemical and kinetic studies, Int. J. Biol. Macromol. 154 (2020) 217–232.
[18] A.A. Khan, H. Ullah, F. Rahim, M. Taha, F. Khan, W. Rehman, A. Wadood, K.
M. Khan, Synthesis, in vitro α-glucosidase and α-amylase activities, and an in silico
molecular docking study of triazinoindole-thiazolidinone hybrid derivatives,
Chem. Data Collect 45 (2023), 101035, https://doi.org/10.1016/j.
cdc.2023.101035.
[19] M. Taha, S. Hayat, F. Rahim, N. Uddin, A. Wadood, M. Nawaz, M. Gollapalli, A.
U. Rehman, K.M. Khan, R.K. Farooq, Exploring thiazole-based Schiff base analogs
as potent α-glucosidase and α-amylase inhibitor: their synthesis and in-silico study,
J. Mol. Struct. 1287 (2023), 135672.
[20] ChemAxon Standardizer, Version 15.9.14.0 Software, ChemAxon, Budapest,
Hungary, 2010.
[21] A. Mauri, AlvaDesc: A Tool to Calculate and Analyze Molecular Descriptors and
Fingerprints in Ecotoxicological QSARs, 2020, pp. 801–820.
[22] I. Sushko, et al., Online chemical modeling environment (OCHEM): web platform
for data storage, model development and publishing of chemical information,
J. Comput. Aided Mol. Des. 25 (2011) 533–554.
[23] J. Sadowski, J. Gasteiger, G. Klebe, Comparison of automatic three-dimensional
model builders using 639 X-ray structures, J. Chem. Inf. Model. 34 (2002)
1000–1008.
[24] A.K. Halder, A.H.S. Delgado, M.N.D.S. Cordeiro, First multi-target QSAR model for
predicting the cytotoxicity of acrylic acid-based dental monomers, Dent. Mater. J.
38 (2022) 333–346.
13
Journal of Molecular Graphics and Modelling 126 (2024) 108640
[25] P. Ambure, R.B. Aher, A. Gajewicz, T. Puzyn, K. Roy, “NanoBRIDGES” software:
open access tools to perform QSAR and nano-QSAR modelling, Chemometr. Intell.
Lab. Syst. 147 (2015) 1–13.
[26] I.V. Tetko, V.Y. Tanchuk, A.E. Villa, Prediction of n-octanol/water partition
coefficients from PHYSPROP database using artificial neural networks and E-state
indices, J. Chem. Inf. Comput. 41 (2011) 1407–1421.
[27] A.K. Halder, Finding the structural requirements of diverse HIV-1 protease
inhibitors using multiple QSAR modelling for lead identification, SAR QSAR
Environ. Res. 29 (2018) 911–933.
[28] A. Golbraikh, A. Tropsha, Beware of q2, J. Mol. Graph. 20 (2002) 269–276.
[29] P.P. Roy, S. Paul, I. Mitra, K. Roy, On two novel parameters for validation of
predictive QSAR models, Molecules 14 (2009) 1660–1701.
[30] W. Yoo, R. Mayberry, S. Bae, K. Singh, Q.P. He, J.W. Lillard, A study of effects of
MultiCollinearity in the multivariable analysis, Int. J. Appl. Sci. Technol. 4 (2014)
9–19.
[31] P.K. Ojha, K. Roy, Comparative QSARs for antimalarial endochins: importance of
descriptor-thinning and noise reduction prior to feature selection, Chemometr.
Intell. Lab. Syst. 109 (2011) 146–161.
[32] K. Roy, S. Kar, P. Ambure, On a simple approach for determining applicability
domain of QSAR models, Chemometr. Intell. Lab. Syst. 145 (2015) 22–29.
[33] P. Tosco, T. Balle, F. Shiri, Open3DALIGN: an open-source software aimed at
unsupervised ligand alignment, J. Comput. Aided Mol. Des. 25 (2011) 777–783.
[34] P. Tosco, T. Balle, Open3DQSAR: a new open-source software aimed at high-
throughput chemometric analysis of molecular interaction fields, J. Mol. Model. 17
(2011) 201–208, https://doi.org/10.1007/s00894-010-0684-x.
[35] A. Waterhouse, M. Bertoni, S. Bienert, G. Studer, G. Tauriello, R. Gumienny, F.
T. Heer, T.A.P. de Beer, C. Rempfer, L. Bordoli, R. Lepore, T. Schwede, SWISS-
MODEL: homology modelling of protein structures and complexes, Nucleic Acids
Res. 46 (2018) W296–W303.
[36] UniProt Consortium, UniProt: the universal protein knowledgebase in 2023,
Nucleic Acids Res. 51 (2023) D523–D531.
[37] G. Wang, J. Z., Peng, X. Li Wang, J. Li, Synthesis, in vitro evaluation and molecular
docking studies of novel triazine-triazole derivatives as potential α-glucosidase
inhibitors, Eur. J. Med. Chem. 125 (2017) 423–429.
[38] J. Christopher, et al., MolProbity: more and better reference data for improved all-
atom structure validation, Protein Sci. 27 (2018) 293–315.
[39] G.M. Morris, R. Huey, W. Lindstrom, M.F. Sanner, R.K. Belew, D.S. Goodsell, A.
J. Olson, AutoDock4 and AutoDockTools4: automated docking with selective
receptor flexibility, J. Comput. Chem. 30 (2009) 2785–2791.
[40] R. Todeschini, V. Consonni, Handbook of Molecular Descriptors, John Wiley &
Sons, Ltd, WILEY-VCH, Germany, 2000, 2000.
[41] K. Roy, I. Mitra, Electrotopological state atom (E-state) index in drug design, QSAR,
property prediction and toxicity assessment, Curr. Comput. Aided Drug Des. 8
(2012) 135–158, https://doi.org/10.2174/157340912800492366.
[42] M. Reutlinger, C.P. Koch, D. Reker, N. Todoroff, P. Schneider, T. Rodrigues,
G. Schneider, Chemically advanced template search (CATS) for scaffold-hopping
and prospective target prediction for ‘orphan’ molecules, Mol. Inform. 32 (2013)
133–138, https://doi.org/10.1002/minf.201200141.
[43] R. Kühne, R.U. Ebert, G. Schüürmann, Chemical domain of QSAR models from
atom-centered fragments, J. Chem. Inf. Model. 49 (2009) 2660–2669.
[44] M.E. Di Ianni, M.E. Del Valle, A.V. Enrique, M.A. Rosella, F. Bruno, L.E. Bruno-
Blanch, A. Talevi, Computer-aided identification of anticonvulsant effect of natural
nonnutritive sweeteners stevioside and rebaudioside A, Assay Drug Dev. Technol.
13 (2015) 313–318.
[45] N.S.H. Moorthy, M.J. Ramos, P.A. Fernandes, Comparative structural analysis of
α-glucosidase inhibitors on difference species: a computational study, Arch.
Pharmazie 345 (2012) 265–274.
[46] M. Duhan, J. Sindhu, P. Kumar, M. Devi, R. Singh, R. Kumar, S. Lal, A. Kumar,
S. Kumar, K. Hussain, Quantitative structure activity relationship studies of novel
hydrazone derivatives as α-amylase inhibitors with index of ideality of correlation,
J. Biomol. Struct. Dyn. 40 (2020) 4933–4953.
[47] K. Diéguez-Santana, A. Puris, O.M. Rivera-Borroto, G.M. Casanola-Martin,
B. Rasulev, H. González-Díaz, A fuzzy system classification approach for QSAR
modeling of α-amylase and α-glucosidase inhibitors, Curr. Comput. Aided Drug
Des. 18 (2022) 469–479.
[48] K. Dieguez-Santana, H. Pham-The, O.M. Rivera-Borroto, A. Puris, H. Le-Thi-Thu, G.
M. Casanola-Martin, A two QSAR way for antidiabetic agents targeting using
α-amylase and α-glucosidase inhibitors: model parameters settings in artificial
intelligence techniques, Lett. Drug Des. Discov. 14 (2017) 8.
[49] S. Ahmadi, Z. Moradi, A. Kumar, A. Almasirad, SMILES-based QSAR and molecular
docking study of xanthone derivatives as α-glucosidase inhibitors, J. Recept. Signal
Transduct. Res. 42 (2021) 361–372.
[50] O. Abchir, O. Daoui, S. Belaidi, M. Ouassaf, F.A. Qais, S. ElKhattabi, S. Belaaouad,
S. Chtita, Design of novel benzimidazole derivatives as potential α-amylase
inhibitors using QSAR, pharmacokinetics, molecular docking, and molecular
dynamics simulation studies, J. Mol. Model. 28 (2022) 4.