COMP 370 |
| The reliable prediction of ligand binding modes and ligand-receptor binding affinities, or at least relative ranks of compounds, is a prerequisite for theoretical approaches to achieve their significant potential in lead optimization. Accurate binding modes can now be obtained with a relatively high level of accuracy when little receptor reorganization is required, as is often the case with ligands of a congeneric series. Free energy calculations, either rigorous as in MC/FEP, or approximate as in physics-based implicit-solvent models, Linear Response, Extended Linear Response, and empirical scoring functions, have been shown to achieve a sufficient level of accuracy for lead optimization in a few isolated cases. To more systematically determine the reliability of the aforementioned free energy methods in predicting and ranking ligands by binding affinities, they have been applied to congeneric series of inhibitors for several targets of pharmaceutical interest. In addition to comparing the reliability of these free energy methods, representative examples will illustrate how computation can be used to drive decision making in lead optimization. |
|
Free Energy Computations in Drug Discovery
9:00 AM-12:40 PM, Thursday, 14 September 2006 Moscone Center -- Room 220/222, Oral
Division of Computers in Chemistry |