Ligand Strain Energy in Large Library Docking

J Chem Inf Model. 2021 Sep 27;61(9):4331-4341. doi: 10.1021/acs.jcim.1c00368. Epub 2021 Sep 1.

Abstract

While small molecule internal strain is crucial to molecular docking, using it in evaluating ligand scores has remained elusive. Here, we investigate a technique that calculates strain using relative torsional populations in the Cambridge Structural Database, enabling fast precalculation of these energies. In retrospective studies of large docking screens of the dopamine D4 receptor and of AmpC β-lactamase, where close to 600 docking hits were tested experimentally, including such strain energies improved hit rates by preferentially reducing the ranks of strained high-scoring decoy molecules. In a 40-target subset of the DUD-E benchmark, we found two thresholds that usefully distinguished between ligands and decoys: one based on the total strain energy of the small molecules and another based on the maximum strain allowed for any given torsion within them. Using these criteria, about 75% of the benchmark targets had improved enrichment after strain filtering. Relying on precalculated population distributions, this approach is rapid, taking less than 0.04 s to evaluate a conformation on a standard core, making it pragmatic for precalculating strain in even ultralarge libraries. Since it is scoring function agnostic, it may be useful to multiple docking approaches; it is openly available at http://tldr.docking.org.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Ligands*
  • Molecular Conformation
  • Molecular Docking Simulation
  • Protein Binding
  • Retrospective Studies

Substances

  • Ligands