Dr.

Usman Ali Ashfaq

Department of Bioinformatics and Biotechnology
Government College University, Faisalabad
 Defined composition with a
pharmacological effect
 Regulated by the Food and Drug
Administration (FDA)
God pharmacy
Serendipity - Penicillin
Serendipity - Aspirin

Serendipity - Aspirin

Molecular Conceptor
 Often molecules are
discovered/synthesized for one
indication and then turn out to be useful
for others
• Tamoxifen (birth control and cancer)
• Interferon-a (hairy cell leukemia and Hepatitis
C)
 Identify disease

Find a drug effective

against disease protein
Isolate protein (2-5 years)
involved in Scale-up
disease (2-5 years)

Preclinical testing
(1-3 years) Human clinical trials
(2-10 years)

Formulation

FDA approval
(2-3 years)
Target Target Lead Lead Preclinical Drug
identification validation identification optimization phase discovery

6-9 years
2-5 years

• Drug discovery is an expensive process involving high R & D cost and

extensive clinical testing
• A typical development time is estimated to be 10-15 years.
 Target identification
• Genomics, gene expression profiling and proteomics

 Target Validation
• Gene knock-out, inhibition assay

 Lead Identification
• High throughput screening, fragment based screening, combinatorial
libraries
 Lead Optimization
• Medicinal chemistry driven optimization, X-ray crystallography, QSAR,
ADME profiling (bioavailability)
 Pre Clinical Phase
• Pharmacodynamics (PD), Pharmacokinetics (PK), ADME, and toxicity
testing through animals
 Clinical Phase
• Human trials
 Bioinformatics

Small molecule
Protein
drug

•Large databases •Large databases

•Not all can be drugs •Not all can be drug targets
•Opportunity for data mining •Opportunity for data mining
techniques techniques
CADD is the chemistry whose major
goals are to create efficient mathematical
approximations and computer programs
that calculate the properties of future
drug molecules and thus helping in the
process of drug design and discovery.
 Comparison of Sequences: Identify targets
 Homology modelling: active site prediction
 Systems Biology: Identify targets
 Databases: Manage information
Insilico methods in Drug Discovery
 Molecular docking
 Virtual High through put screening.
 QSAR (Quantitative structure-activity relationship)
 Pharmacophore mapping
 Fragment based screening
• Docking is the identification of the
low-energy binding modes of a small
molecule, or ligand, within the active
site of a macromolecule, or receptor,
whose structure is known.
• Scoring Function
• Optimization Methods
1. Protein-Ligand Docking:
 Ligand is flexible but the receptor protein is rigid
 Interaction produces conformational changes in
ligand
2. Protein-Protein Docking:
 Both molecules are rigid
 Interaction produces no change in conformation
 Similar to lock-and key model
Protein-Protein Docking
Protein-ligand docking
 Computational method that mimics the binding of a ligand to
a protein
 MOE-Dock
 FlexX
 GOLD
 AutoDOCK
 FRED
 Hammerhead
 FLOG
 DOCK
Hepatitis C Virus
Liver diseases

World 3% (270 million )

Pakistan 6% (10 million )

Genetically Highly Variable

Genotype: Pakistan 3a World 1a

Interferon and Ribavirin/ sofosbuvir

Hepatitis C Virus Virology

P7

Ion
channel
Helps in identifying all antigens of
pathogens and also allows the discovery
of novel antigens.

Gene sequences of viral pathogens have

been used to develop synthetic peptides,
used for vaccines against chronic
infections such as Hepatitis B, Hepatitis C
and HIV.
Protein retrieval & Exomembrane Antigenicity
Structure epitopes were prediction using
prediction further analyzed VaxiJen v2. 0

B-cell epitope Transmembrane Epitopes with high

prediction using topology using antigenicity were
BCPREDS TMHMM screened

Disco Top 2.0 T-cell epitope Conservation

Server for B-cell prediction using analysis using CLC
prediction using Propred-1 and workbench and
3D structure Propred IEDB server
A total of four conserved antigenic B cell
epitopes, 5 MHC class I binding peptides
and 5 MHC class II binding peptides
were predicted that were well conserved
with other regions.
 Similarly, HCVE2 protein of Pakistani
origin was analyzed using various
bioinformatics tools.
 Exo-membrane Antigenecity
Sample
epitopes were prediction using
collection
selected Vexijen server

Transmembrane
Most antigenic
topology
RNA isolation epitopes were
checked using
screened
TMHMM

B-cell epitope Conservation

cDNA synthesis prediction using analysis using
BCPred IEDB server

Amplification T-cell epitope

and cloning of prediction using
the HCV E2 gene Epijen v1.0
Atotal of 3 B-cell and 3 T-cell epitopes
were found to be highly conserved
among HCV 3a and 1a genotype
(Most prevalent genotypes in Pakistan).
HCV pseudoparticle production GNA as antiviral agent

Interaction of Asn18 of HCV Interaction of Asn18 of HCV

with Asn30 of 1JPC GNA lectin with Asn61 of 1JPC GNA lectin
 Inthis study, sequence of Dengue virus
NS3 protein was analyzed to draw a
global consensus sequence (conserved
among all seroytpes).
 Potential conserved domains were
identified.
 Phylogenetic analysis to compare with
sequence of other regions.
 Conserved
Protein
domain
sequences
identification

Peptide
Multiple
designing from
Sequence
conserved
alignment (MSA)
regions

Consensus Global
sequence consensus
identification sequence
 Canthin-6-one 9-O-
betaglucopyranosid

Kushenol W

Kushenol K
 Combination of In-vitro + In-silico techniques
were used to screen effective inhibitors against
HIV-1 reverse transcriptase.

 N'-substituted benzylidene-2-(4-methyl-5,5-
dioxido-3-phenylbenzo[e]pyrazolo[4,3-
c][1,2]thiazin-1(4H)-yl)acetohydrazides series
was screened.
 In-vitro results
In-vitro
were matched
synthesis &
with in-silico
screening
results

Top
Docking with
conformation
HIV-1 reverse
selection on the
transcriptase
basis of S score
 Two series of fifteen N-substituted
benzyl/phenyl-2-(3,4-dimethyl-5,5-
dioxidopyrazolo[4,3-c][1,2]benzothiazin-
2(4H)-yl)acetamides were screened for
anti-HIV-1 activity and cytotoxicity
 In-vitro results
In-vitro synthesis were matched
& screening with in-silico
results

Docking with Top

HIV-1 reverse conformation
transcriptase selection on the
using MOE basis of S score
Binding modes of the compound 6e (magenta), 6g (cyan) and 6i (purple) in HIV-1
reverse transcriptase NNRTI binding pocket. Nevirapine (yellow) is the co-crystal
structure with in HIV-1 reverse transcriptase.
MAPS DATABASE
MAPS Database Search Options
Antibacterial, Antiviral,
Anti-inflammatory, Cardial
Activities protective, Urease
inhibitory,
Antifungal, Antisickling,
Phytochemic
Larvacidal, Insecticidal,
als Antiprotozoal etc….

Structures
Terpenoids, Steriods,
Saponins,Aromatic,
Alkaloids,
Test Targets Flavonoids…

Literature Bacteria, Viruses,

Fungi, Tumor Cells
Larva, ..etc
 MAPS Database MP3D
Literature References 450 1354
Phytochemical Records 2200 7309
Targets 150 250
Activities 41 91
Phytochemical 1200 3600
Structures
Plants 500 1022
Database Download No YES
Option
Cost FREE FREE
Update Weekly basis Weekly basis
Ready to dock Library No YES (2295)
Supplementary Data No YES
Thanks