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

Editorial: J. Am. Chem. Soc., 118(16), p.3959-3969, 1996.

Rezumat:

VALIDATE is a hybrid approach to predict the binding affinity of novel ligands for receptors of known three-dimensional structure. This approach calcs. physicochem. properties of the ligand and the receptor-ligand complex to est. the free energy of binding. The enthalpy of binding is calcd. by mol. mechanics while properties such as complementary hydrophobic surface area are used to est. the entropy of binding through heuristics. A diverse training set of 51 cryst. complexes was assembled, and their relevant physicochem. properties were computed. These properties were analyzed by partial least squares (PLS) statistics, or neural network anal. (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 compd. not included in the training set, 13 HIV protease inhibitors fit to HIV-1 protease, and 11 thermolysin inhibitors fit to thermolysin.

Cuvinte cheie: Conformation (ligand), Conformation (receptor), Hydrophobicity, Molecular association, QSAR (Structure-Activity Relationships), Receptor-binding, Scoring functions