title: Large-scale application of high-throughput molecular mechanics with Poisson-Boltzmann surface area for routine physics-based scoring of protein-ligand complexes.
abstract: We apply a high-throughput formulation of the molecular mechanics with Poisson-Boltzmann surface area (htMM-PBSA) to estimate relative binding potencies on a set of 308 small-molecule ligands in complex with the proteins urokinase, PTP-1B, and Chk-1. We observe statistically significant correlation to experimentally measured potencies and report correlation coefficients for the three proteins in the range 0.72-0.83. The htMM-PBSA calculations illustrate the feasibility of procedural automation of physics-based scoring calculations to produce rank-ordered binding-potency estimates for protein-ligand complexes, with sufficient throughput for realization of practical implementation into scientist workflows in an industrial drug discovery research setting.
authors.affiliation: Structural Biology, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Brown
authors.forename: Steven W
authors.initials: SW
authors.lastname: Muchmore
mesh_terms: D000071877:Checkpoint Kinase 1; D002626:Chemistry, Pharmaceutical / Q000379:methods; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D008962:Models, Theoretical; D016012:Poisson Distribution; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry
chemical_list: D008024:Ligands; D011506:Proteins; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D014568:Urokinase-Type Plasminogen Activator