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[摘要]：The identification of lead mols. using computational modeling often relies on approx., high-throughput approaches, of limited accuracy. The authors show here that, with a methodol. the authors recently developed, it is possible to predict the relative binding free energies of structurally diverse ligands of the estrogen receptor-a using a rigorous statistical thermodn. approach. Predictions obtained from the simulations with an explicit solvation model are in good qual. agreement with exptl. data, while simulations with implicit solvent models or rank ordering by empirical scoring functions yield predictions of lower quality. In addn., it is shown that free energy techniques can be used to select the most likely binding mode from a set of possible orientations generated by a docking program. It is suggested that the free energy techniques outlined in this study can be used to rank-order, by potency, structurally diverse compds. identified by virtual screening, de novo design or scaffold hopping programs. |
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