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Book of Abstracts: Albany 2007

category image Albany 2007
Conversation 15
June 19-23 2007

Sketching A Physico-Chemical Pathway from Gene to Drug In Silico

The world wide genome sequencing efforts and the concurrent developments in scientific software implementations on massively parallel computer architectures grant us the opportunity to dream that drug design could be undertaken against suitable biomolecular targets to develop individualized medicine almost in an automated way. Currently, however, without the help of any database, an inspection of a DNA sequence does not tell us whether it is likely to be a gene and if it is a gene what the likely three dimensional structure of its protein product is. Also drug design softwares fall short of expectations even if the structures of drug targets are known.

Addressing the above issues from a physico-chemical perspective, we have developed a novel semi-empirical model for whole genome analysis (ChemGenome) based on DNA energetics, an all atom energy based computational protocol for narrowing down the search space for locating tertiary structures of small globular proteins (Bhageerath) and a binding free energy based methodology for active site directed lead molecule design (Sanjeevini). The ChemGenome could distinguish genes from non-genes in 331 bacterial genomes and 20 eukaryotic genomes with > 90% accuracy. The start and stop site prediction accuracies of Chemgenome are either at par or exceed the current standards. Bhageerath could successfully bracket native-like structures to within 3 to 6 Å in the 10 lowest energy structures for 50 small alpha helical globular proteins. Also the Bhageerath algorithms have been seen to scale linearly on a Bluegene 1024 processor cluster. The Sanjeevini drug design protocol could sort drugs from non-drugs for COX-2 and Estrogen receptor. Progresses recorded in the areas of genome analysis, protein structure prediction and drug design and the software tools developed and made freely accessible at www.scfbio-iitd.res.in together with promises there of will be presented.

References and Footnotes
  1. Dutta, S., Singhal, P., Agrawal, P., Tomer, R., Kritee, Khurana, E., and Jayaram. B. Journal of Chemical Information & Modelling 46, 78-85 (2006).
  2. (a) Narang, P., Bhushan, K., Bose, S., and Jayaram, B. Phys Chem Chem Phys 7, 2364 (2005); (b) Narang, P., Bhushan, K., Bose, S., and Jayaram, B. J Biomol Struct Dyn 23, 385-4006 (2006); (c) Jayaram et al. Nucleic Acid Res 34, 6195-6204 (2006).
  3. (a) Latha, N. and Jayaram, B. Drug Design Reviews-Online 2, 145 (2005); (b) Jain, T. and Jayaram, B. FEBS Letters 579, 6659 (2005); (c) Jain, T. and Jayaram, B. Proteins: Structure, Function & Bioinformatics, in press (2007); (d) Shaikh, S. and Jayaram. B. J Med Chem, in press (2007); (e) Shaikh, S., Jain. T., Sandhu, G., Latha, N., and Jayaram., B. Current Pharmaceutical Design, in press (2007).

B. Jayaram

Department of Chemistry & Supercomputing Facility for Bioinformatics & Computational Biology
Indian Institute of Technology
Hauz Khas, New Delhi-110016, India

Email: bjayaram@chemistry.iitd.ac.in