Automated docking with grid‐based energy evaluation

TLDR

Generating feasible binding orientations of small molecules in known protein sites is essential for ligand design. The authors present a method that combines rapid geometric docking with molecular‑mechanics energy evaluation to facilitate database searches for potential lead compounds. The method precomputes receptor‑dependent energy terms on a 3‑D grid, enabling rapid evaluation of docking poses. The force‑field scoring accurately recovers near‑native orientations in four redocking tests, outperforming steric‑only or electrostatic‑only scoring functions.

Abstract

Abstract The ability to generate feasible binding orientations of a small molecule within a site of known structure is important for ligand design. We present a method that combines a rapid, geometric docking algorithm with the evaluation of molecular mechanics interaction energies. The computational costs of evaluation are minimal because we precalculate the receptor‐dependent terms in the potential function at points on a three‐dimensional grid. In four test cases where the components of crystallographically determined complexes are redocked, the “force field” score correctly identifies the family of orientations closest to the experimental binding geometry. Scoring functions that consider only steric factors or only electrostatic factors are less successful. The force field function will play an important role in our efforts to search databases for potential lead compounds.