In Silico Discovery and Development of Bio Therapeutics

In Silico Discovery and Development of Bio. Therapeutics • • • 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

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 Mimotopes for diseases diagnostics Structure determination: Biomolecules Natural, non-natural , modified bonds Synthesis: Phase display, SPSS, Codon Suffeling Structure prediction: Natural, non-natural , modified bonds Natural bioactive peptides from metagenomics Mimotopes for B/T epitopes ADMET: Proteolytic enzymes, Half-life Peptide Structure, docked structure Mimicking of Drug Molecules Size Optimization for function/Str. Oral Delivery : Trans. & Adjuvant

IMTECH Participants • • • G P S Raghava Balvinder Singh Manoj Kumar Sri. Krishna Subramanian Ashish Gangualy G C Varshney S Kumaran Hemraj Nandanwar Pushpa Aggrawal Alok Mondal • Javed Agrewala • • R. Kishore Alka Rao Charu Sharma Ankita Manoj Rajee Shekar Majumdar Pawan Gupta Saumya Raychaudhuri

Other CSIR Participants • • • • Kunwar P. Singh, M I Siddiqi, Somdatta Sinha, Vidya Gupta, Anu Raghunathan, R K Sharma, Amit Mishra, Amit Nagotra, Ravi Shankar, S. Ramachandra, Debasis Dash Anshu Bhardwaj G N Sastry, USN Murthy, Sudarsan Kumar, IITR CDRI CCMB NCL CDRI IIIM CDRI IHBT IGIB 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 3 D-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 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 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 • • To develop bioinformatics tools for Viral RNAi To develop viral si. RNA/mi. RNA databases To develop mutated viral si. RNA/mi. RNA databases To develop algorithm to predict highly efficacious viral si. RNA • To predict host factor important for viral RNAi HIV-1 Subtype C Protease and Reverse Transcriptase Amino Acid Covariation: And Prediction of HIV-1 C drug response from the RT and protease amino acid sequences:

Anu Raghunathan and Rajesh Singh, NCL • • 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 3 D 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