The growing genomic and proteomic sequence/structural databases trigger high expectations for a rapid and successful treatment of diseases and disorders. In the current biological information rich and functional knowledge poor scenario, the feasibility of creating an automated genomes to hits (G2H) assembly line to cut down the cost and time in drug discovery is discussed. The G2H computational pathway involves several challenging research areas viz. functional annotation of genomes, identification of druggable targets, prediction of three-dimensional structures of protein targets from their amino acid sequences, and hit molecule generation for these targets followed by a transition from bench to bedside. We describe here the “G2H In Silico“ strategy (called Dhanvantari) and illustrate it on Chikungunya virus (CHIKV). G2H is a novel pathway incorporating a series of steps such as gene prediction (Chemgenome), protein tertiary structure determination (Bhageerath), automated active site identification, rapid hit molecule generation followed by atomic level docking and scoring of hits to arrive at lead compounds (Sanjeevini). The current state of the art for each of the steps in the pathway will be high-lighted and the results will be presented and discussed.

Related References

Chemgenome: (a) Dutta S, Singhal P, Agrawal P, Tomer R, Khurana KE & Jayaram B (2006). A Physicochemical model for analyzing DNA sequences. J. Chem. Inf. Model 46, 78-85; (b) Singhal P, Jayaram B, Dixit SB & Beveridge DL (2008). Prokaryotic gene finding based on physicochemical characteristics of codons calculated from molecular dynamics simulations. Biophys J. 94, 4173-83; (c) Khandelwal G & Jayaram B (2012). DNA-water interactions distinguish messenger RNA genes from transfer RNA genes. J. Am. Chem. Soc. 134, 8814-16; (d) Khandelwal G, Gupta J & Jayaram B (2012). DNA energetics based analyses suggest additional genes in prokaryotes. J. Bio Sc. 37, 433-44.

Bhageerath: (a) Jayaram B, Bhushan K, Shenoy SR, Narang P, Bose S, Agrawal P, Sahu D, Pandey V (2006). Bhageerath: an energy based web enabled computer software suite for limiting the search space of tertiary structures of small globular proteins. Nucleic Acid Res. 34, 6195-204; (b) Shenoy SR & Jayaram B (2010). Proteins: sequence to structure and function-current status. Curr. Protein Pept. Sci. 11, 498-514; (c) Mittal A, Jayaram B, Shenoy S & Bawa TS (2010). A stoichiometry driven universal spatial organization of backbones of folded proteins: are there Chargaff's rules for protein folding? J. Biomol. Struc. Dyn. 28, 133-142; (d) Jayaram B, Dhingra P, Lakhani B & Shekhar S (2012). Bhageerath-Targeting the near impossible: Pushing the frontiers of atomic models for protein tertiary structure prediction. J. Chem. Sci. 124, 83-91.

Sanjeevini: (a) Jain T & Jayaram B (2005). An all atom energy based computational protocol for predicting binding affinities of protein-ligand complexes. FEBS Lett. 579, 6659-66; (b) Shaikh SA & Jayaram B (2007). A swift all-atom energy-based computational protocol to predict DNA-ligand binding affinity and ∆Tm. J. Med. Chem. 50, 2240-44; (c) Jayaram B, Singh T, Mukherjee G, Mathur A, Shekhar S & Shekhar V (2012). Sanjeevini: a freely accessible web-server for target directed lead molecule discovery. BMC Bioinformatics 13, S7; doi:10.1186/1471-2105-13-S17-S7; (d) Soni A, Menaria K, Ray P & Jayaram B (2013). Genomes to Hits in Silico - A Country Path Today, A Highway Tomorrow: A Case Study of Chikungunya. Curr. Pharma. Des, in press.