In Silico Discovery and Development
of BioTherapeutics
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Background
Past decade for extracting knowledge from huge sequence data
Major issues addressed: Annotation, Structure Prediction, drug target
Tools developed to understand biology
Limited work on applied bioinformatics
Major problem is synergy between Biologist and Bioinformaticians
Main Objective
Application oriented research leads to drug, vaccine or diagnostics
Studying complete pathway (TargetInhibitorQSARADMET)
Experimental Validation (Biologist  Bioinformaticians)
Direct or Indirect benefit to public
Detailed Objectives
 Identification of and development of novel drug/vaccine targets
 Discovering natural therapeutic molecules from biological databases
 Designing of peptide/protein based inhibitors against potential targets
 In silico design of molecules that can serve as vaccines, drugs and biomarkers
 Designer biomolecules with the incorporation of desired function and structure
 Novel algorithms for design and development of biotherapeutics
 Models for predicting ADMET properties of biomolecules
 Drug delivery by biodegradable nanoparticles
 Mimicking of biomolecular structure and function
 Experimental validation of promising in silico predictions
Theoretical models for supportin g findings of experimentalist
Drug/inhibitor/vaccine/
Disease Diagnostics
Peptide-Protein
Interaction
Adaptive Immunity: B-cell,
T-cell Epitope
Innate Immunity: Toll-like
receptors
Anti-(bacterial , microbial,
cancer, viral) peptides
Structure determination:
Natural, non-natural ,
modified bonds
Structure prediction:
Natural, non-natural ,
modified bonds
Natural bioactive peptides
from metagenomics
Mimotopes for B/T epitopes
ADMET: Proteolytic
enzymes, Half-life
Mimotopes for diseases
diagnostics
Biomolecules
Synthesis: Phase display,
SPSS, Codon Suffeling
Peptide Structure,
docked structure
Mimicking of Drug Molecules
Size Optimization
for function/Str.
Oral Delivery : Trans.
& Adjuvant
IMTECH Participants
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G P S Raghava
Balvinder Singh
Manoj Kumar
SriKrishna Subramanian
Ashish Gangualy
G C Varshney
S Kumaran
Hemraj Nandanwar
Pushpa Aggrawal
Alok Mondal
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Javed Agrewala
R. Kishore
Alka Rao
Charu Sharma
Ankita
Manoj Rajee
Shekar Majumdar
Pawan Gupta
Saumya Raychaudhuri
Other CSIR Participants
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Kunwar P. Singh,
M I Siddiqi,
Somdatta Sinha,
Vidya Gupta,
Anu Raghunathan,
R K Sharma,
Amit Mishra,
Amit Nagotra,
Ravi Shankar,
Ravi Shankar,
S. Ramachandra,
Debasis Dash
Anshu Bhardwaj
G N Sastry,
USN Murthy,
Sudarsan Kumar,
IITR
CDRI
CCMB
NCL
NCL
CDRI
CDRI
IIIM
CDRI
IHBT
IGIB
IGIB
IGIB
IICT
IICT
NBRI
Proposals and impact statement
Dr. Alka Rao - IMTECH
Cataloguing and Creation of a Database of
glycoproteins and deducing rules/patterns thereof that
could have biological significance.
First ever database exclusively focused on a single post
translational modification of proteins namely
glycosylation. This database will be a ready reference to
researchers in the field of glycoproteomics and for
research in the fields of disease diagnosis, pathogenesis
and understanding of host pathogen interactions.
Ashish Ganguly - IMTECH
• Web-server to predict drug loading and slow-release profile from biodegradable nanoparticles.
• 1. Experimentally quantify the maximum drug loading capacity of
some
• bio-degradable nanoparticles with varying particle size and crosslinking
• nature, with focus on PLGA nanoparticles.
• 2. Experimentally monitor the Higuchi or Burst-release and
Degradation or Slow
• release profiles of drug particles.
• 3. Experimentally monitor the decrement in particle size of the naive
and
• drug-loaded nanoparticles.
• 4. Correlate the drug shape, size, density with loading capacity of
• nanoparticles of varying sizes and chemical nature.
• 5. Formulate a mathematical model of loading and release profile.
• 6. Test mathematical model by experiments and publish results.
Dr. M. I. Siddiqi, CDRI, Lucknow
Computational biology and in silico modeling
approaches for design of new therapeutics.
• Development and applications of new approaches
for pathway modeling to identify new drug targets
in various human pathogens and target assessment.
• Structure-based pharmacophore hypothesis
generation and in silico screening and modeling of
drug target interaction with identified leads.
• Development of computational predictive models
and tools and optimization of pharmacophores using
3D-QSAR methods including ADMET predictions.
Charu Sharma - IMTECH
Studying the interactions between Mtb and macrophage
at the level of proteins.
• In the first step, with the help of Bioinformatics the most
probable interactions between Mtb proteins and
macrophage proteins could be predicted. These
predicted interactions further can be validated by
various biological methods as mentioned above.
• The second step is the prediction of the disruption of the
confirmed protein-protein interactions which could be of
great use for the therapeutic purpose. And finally the
biological assay to confirm and to study the outcome of
these disruptions.
Amit Nargotra - Jammu
To develop a web-enabled database on
natural products and protein folds with
advanced structural search feature
• A comprehensive web enabled database on
natural products and protein folds with
structural and sub-structural search
provision.
• Patent, Copyright and publications.
• Human Resource Development.
Grish Varshney - IMTECH
a) Development of Computer-Aided vaccines,
diagnostics and drugs against
• malaria
• and tuberculosis.
b) Prediction and validation of specificities
and cross reactivities of clinically important
monoclonal antibodies.
Hemraj Nandanwar
- IMTECH
Development of Computer-aided
Biomolecules based drugs, vaccines and
disease diagnostics.
Studying resistance against beta-lactam
antibiotics and develop better antibiotics.
Development of indirect anti-diabetic agent,
which may be used as slimming or antiobesity agent.
R. Kishore - IMTECH
• 1. Computational or theoretical structural analysis of peptides
and related
• molecules.
• 2. crystallization and X-ray diffraction analysis of peptide and
• peptide based based biomolecules.
• 3. Chemical synthesis of peptides and peptide based-molecules.
• 4. Solution structural analysis of peptides and peptide based
molecules
• using various spectroscopic techniques like:
• a. One- and two-dimensional NMR
• b. FT-IR and Raman spectroscopic techniques
• c. CD spectroscopy
• d. Fluorescence and UV spectroscopic techniques
S. Kumaran, IMTECH
Decoding The Signaling Networks of
Allostery in Proteins By Molecular
Dynamics Simulations
• Results obtained would provide information on
molecular basis of long-range interaction
between regulatory binding site and functional
site of the protein. Functional mutagenesis and
rational design of ligands would validate the
model and help us detect the signal
propagation pathways in proteins. Completion
of our work on a protein system would result
in publication in high quality journals.
Manoj Kumar - IMTECH
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To develop bioinformatics tools for Viral RNAi
To develop viral siRNA/miRNA databases
To develop mutated viral siRNA/miRNA databases
To develop algorithm to predict highly efficacious
viral siRNA
• To predict host factor important for viral RNAi
HIV-1 Subtype C Protease and Reverse
Transcriptase Amino Acid Covariation:
And
Prediction of HIV-1C drug response from the RT
and protease amino acid sequences:
Anu Raghunathan and Rajesh Singh, NCL
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Integration Of A Genome-Scale Structural View
Of Pathogens With Metabolic Network
Reconstruction To Unravel Novel Drug Targets
Genome scale metabolic model of the pathogen to
compute and predict function accurately.
Analyses and interpretation of all folds and domains
in a pathogen and their representation in 3D space in
the cell
New insights into mechanisms of infection and
probable drug targets.
A scalable methodology to apply to other pathogens.
Vidya - NCL
• Bioinformatics and functional genomics approaches
to decipher the bread making quality potential of
hexaploid wheat
• Database of bread-making quality (BMQ) genes from
wheat
• Software for comparative genomics
• New SSRs and gene specific markers for BMQ in wheat
• Linkage map saturated with markers flanking the BMQ
related gene targets
Pawan Gupta - IMTECH
• In silico design of Peptide Nucleic Acid (PNA) for
Mycobacterium tuberculosis specific Antigene &
Antisense approach.
Peptide nucleic acid, an artificially synthesized
polymer is similar to DNA or RNA and is used in
biological research and medical treatments. Also,
plethora of literature is there about many cell
penetrating peptides that do no recognize cell/
membrane barriers. Our idea is to conjugate antigene and anti-sense property of PNA, GNA, LNA
etc molecule with properties of CPP and some other
membrane traversing peptides and proteins to
combat intracellular parasites.
Manoj raje - IMTECH
• Evaluation of : Designer biomolecules
with the incorporation of desired
function and structure, Drug delivery by
biodegradable nanoparticles and
Experimental validation of promising in
silico predictions
Participants wish list
• S Ramachandran, IGIB (Drug target and experimental validation)
• Sudarsan Kumar, NBRI (Plan Database)
• Debsis