VALIDATE: A new method for the receptor-based prediction of binding affinities of novel ligands

Richard D. Head, Mark L. Smythe, Tudor I. Oprea, Chris L. Waller, Stuart M. Green, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

233 Scopus citations

Abstract

VALIDATE is a hybrid approach to predict the binding affinity of novel ligands for receptors of known three-dimensional structure. This approach calculates physicochemical properties of the ligand and the receptor-ligand complex to estimate the free energy of binding. The enthalpy of binding is calculated by molecular mechanics while properties such as complementary hydrophobic surface area are used to estimate the entropy of binding through heuristics. A diverse training set of 51 crystalline complexes was assembled, and their relevant physicochemical properties were computed. These properties were analyzed by partial least squares (PLS) statistics, or neural network analysis (SONNIC), to generate models for the general prediction of the affinity of ligands with receptors of known three-dimensional structure. The ability of the model to predict the affinity of novel complexes not included in the training set was demonstrated with three independent test sets: 14 complexes of known three-dimensional structure including 3 DNA complexes, a class of compound not included in the training set, 13 HIV protease inhibitors fit to HIV-1 protease, and 11 thermolysin inhibitors fit to thermolysin.

Original languageEnglish
Pages (from-to)3959-3969
Number of pages11
JournalJournal of the American Chemical Society
Volume118
Issue number16
DOIs
StatePublished - Apr 24 1996

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