Molecular speleology: the exploration of crevices in proteins for prediction of binding sites, design of drugs and analysis of surface recognition

A method is described for analyzing molecular-surface complementarity, including the binding of ligands to proteins or the interaction of elements of secondary structure in protein interiors. A computer program can identify and model molecules that satisfy general criteria for good binding affinity. Computational tests are presented. This approach is likely to have useful application in the analysis of surface recognition in proteins, including the identification of binding sites, and in the design of drugs for specific targets, by (i) suggesting potential pharmacophores to the medicinal chemist for further computational analysis or laboratory testing, (ii) suggestion of derivatives of a known ligand to enhance its affinity, or (iii) searching a data base of known drugs for a match to the predicted ligand.