MEDI 85 |
| To understand the binding modes of benzimidazole series of compounds as well as to get a deeper insight into the structure-activity relationship, we performed docking studies, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). All the compounds were docked in the allosteric binding site of a recently developed crystal structure of HCV NS5B polymerase (PDB ID: 2dxs). Furthermore, docking experiments suggested the importance of hydrogen bonding interaction between the carboxamide and the carboxyl carbonyl oxygen atoms of the inhibitors and the guanidine group of Arg503. By exporting the docked conformations to Sybyl, 3D-QSAR models with cross-validated r2cv values of 0.622 and 0.759 for CoMFA and CoMSIA, respectively, were built. Validation of the models with an external set of compounds yielded satisfactory predictive r2 values of 0.766 and 0.835 for CoMFA and CoMSIA, respectively. The best CoMSIA model indicated that electrostatic and H-bond acceptor interactions (~80%) contribute more towards biological activity than the steric interactions. These statistically significant models can serve as guides for the rational design of potent inhibitors of HCV NS5B polymerase. A detail discussion of the 3D-QSAR and the structure-based computational results of these compounds will be provided. |
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Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |