Target flexibility in molecular recognition.
Induced-fit effects are well known in the binding of small molecules to proteins and other macromolecular targets. Among other targets, protein kinases are particularly flexible proteins, so that such effects should be considered in attempts at structure-based inhibitor design for kinase targets. This paper outlines some recent progress in methods for including target flexibility in computational studies of molecular recognition. A focus is the "relaxed complex method," in which ligands are docked to an ensemble of conformations of the target, and the best complexes are re-scored to provide predictions of optimal binding geometries. Early applications of this method have suggested a new approach to the development of inhibitors of HIV-1 Integrase.
McCammon
J Andrew
JA
Howard Hughes Medical Institute, La Jolla, CA 92093-0365, USA. jmccammon@ucsd.edu
D003198:Computer Simulation; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; D011506:Proteins; D019427:HIV Integrase