Large-Scale Application of High-Throughput Molecular Mechanics with Poisson−Boltzmann Surface Area for Routine Physics-Based Scoring of Protein−Ligand Complexes

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.