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Empirical free energy as a target function in docking and design: application to HIV‐1 protease inhibitors
Author(s) -
King Benjamin L.,
Vajda Sandor,
DeLisi Charles
Publication year - 1996
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(96)00276-1
Subject(s) - docking (animal) , conformational entropy , searching the conformational space for docking , solvation , chemistry , molecular dynamics , hiv 1 protease , computational chemistry , entropy (arrow of time) , biological system , computer science , computational biology , protein structure , stereochemistry , protease , enzyme , biochemistry , physics , thermodynamics , biology , molecule , medicine , nursing , organic chemistry , solvent
Structure‐based drug design requires the development of efficient computer programs for exploring the structural compatibility of various flexible ligands with a given receptor. While various algorithms are available for finding docked conformations, selecting a target function that can reliably score the conformations remains a serious problem. We show that the use of an empirical free energy evaluation method, originally developed to characterize protein‐protein interactions, can substantially improve the efficacy of search algorithms. In addition to the molecular mechanics interaction energy, the function takes account of solvation and side chain conformational entropy, while remaining simple enough to replace the incomplete target functions used in many drug docking and design procedures. The free energy function is used here in conjunction with a simple site mapping‐fragment assembly algorithm, 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 Å, compared to 1.69 Å using an energy target function, and also accurately predict the free energy shifts obtained with a series of five trimeric hydroxyethylene isostere analogs.