The relaxed complex method: Accommodating receptor flexibility for drug design with an improved scoring scheme

Abstract

An extension of the new computational methodology for drug design, the “relaxed complex” method (J.‐H. Lin, A. L. Perryman, J. R. Schames, and J. A. McCammon, Journal of the American Chemical Society, 2002, vol. 24, pp. 5632–5633), which accommodates receptor flexibility, is described. This relaxed complex method recognizes that ligand may bind to conformations that occur only rarely in the dynamics of the receptor. We have shown that the ligand–enzyme binding modes are very sensitive to the enzyme conformations, and our approach is capable of finding the best ligand enzyme complexes. Rapid docking serves as an efficient initial filtering method to screen a myriad of docking modes to a limited set, and it is then followed by more accurate scoring with the MM/PBSA (Molecular Mechanics/Poisson Boltzmann Surface Area) approach to find the best ligand–receptor complexes. The MM/PBSA scorings consistently indicate that the calculated binding modes that are most similar to those observed in the x‐ray crystallographic complexes are the ones with the lowest free energies. © 2002 Wiley Periodicals, Inc. Biopolymers 68: 47–62, 2003