EMPIRICAL FREE-ENERGY AS A TARGET FUNCTION IN DOCKING AND DESIGN - APPLICATION TO HIV-1 PROTEASE INHIBITORS

Structure-based drug design requires the development of efficient comp uter programs for exploring the structural compatibility of various fl exible ligands with a given receptor, While various algorithms are ava ilable for finding docked conformations, selecting a target function t hat can reliably score the conformations remains a serious problem, We show that the use of an empirical free energy evaluation method, orig inally developed to characterize protein-protein interactions, can sub stantially improve the efficacy of search algorithms, In addition to t he molecular mechanics interaction energy, the function takes account of solvation and side chain conformational entropy, while remaining si mple enough to replace the incomplete target functions used in many dr ug docking and design procedures, The free energy function is used her e in conjunction with a simple site mapping-fragment assembly algorith m, for docking the MVT-101 non-peptide inhibitor to HIV-1 protease, In particular, we predict the bound structure with an all atom RMSD of 1 .21 Angstrom, compared to 1.69 Angstrom using an energy target functio n, and also accurately predict the free energy shifts obtained with a series of five trimeric hydroxyethylene isostere analogs.