In pursuit of virtual lead optimization: the role of the receptor structure and ensembles in accurate docking.

ABSTRACT: Accurate ranking during in silico lead optimization is critical to drive the generation of new ligands with higher affinity, yet it is especially difficult because of the subtle changes between analogs. In order to assess the role of the structure of the receptor in delivering accurate lead ranking results, we docked a set of forty related inhibitors to structures of one species of dihydrofolate reductase (DHFR) derived from crystallographic, NMR solution data, and homology models. In this study, the crystal structures yielded the superior results: the compounds were placed in the active site in the conserved orientation and the docking scores for 80% percent of the compounds clustered into the same bins as the measured affinity. Single receptor structures derived from NMR data or homology

SUBMITTER: Bolstad ES 

PROVIDER: S-EPMC3644990 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature