QM/MM as a tool in fragment based drug discovery. A cross-docking, rescoring study of kinase inhibitors

Gleeson, M. Paul; Gleeson, Duangkamol

doi:10.1021/ci900022h

QM/MM as a tool in fragment based drug discovery. A cross-docking, rescoring study of kinase inhibitors

Author(s)

Gleeson, M. Paul

Gleeson, Duangkamol

Date Issued

June 22, 2009

Type

Article

DOI

10.1021/ci900022h

Abstract

The use of QM/MM based methods to optimize and rescore GOLD derived cross-docked protein-ligand poses has been investigated using a range of fragment-like kinase inhibitors where experimental data have been reported. Particular emphasis has been placed on rationalizing the potential benefits of the method in the increasingly popular fragment based drug discovery area. The results of this cross-docking, rescoring study on 9 protein ligand complexes suggest that the hybrid QM/MM calculations could prove useful in kinase fragment based drug discovery (FBDD). B3LYP/6-31G^**//UFF derived enthalphies allow us to identify the correct X-ray pose from a range of plausible decoys 77% of the time, almost a doubling of the retrieval rate compared to GOLD (44%). In addition, this method provides us with a means to rapidly and accurately generate virtual protein-ligand complexes that will allow a program team to probe the existing interactions between the ligand and protein and search for additional interactions. © 2009 American Chemical Society.

Citation

Journal of Chemical Information and Modeling, 49(6), 1437-1448, 2009