Getting Docking into Shape Using Negative Image-Based Rescoring

J Chem Inf Model. 2019 Aug 26;59(8):3584-3599. doi: 10.1021/acs.jcim.9b00383. Epub 2019 Jul 24.

Abstract

The failure of default scoring functions to ensure virtual screening enrichment is a persistent problem for the molecular docking algorithms used in structure-based drug discovery. To remedy this problem, elaborate rescoring and postprocessing schemes have been developed with a varying degree of success, specificity, and cost. The negative image-based rescoring (R-NiB) has been shown to improve the flexible docking performance markedly with a variety of drug targets. The yield improvement is achieved by comparing the alternative docking poses against the negative image of the target protein's ligand-binding cavity. In other words, the shape and electrostatics of the binding pocket is directly used in the similarity comparison to rank the explicit docking poses. Here, the PANTHER/ShaEP-based R-NiB methodology is tested with six popular docking softwares, including GLIDE, PLANTS, GOLD, DOCK, AUTODOCK, and AUTODOCK VINA, using five validated benchmark sets. Overall, the results indicate that R-NiB outperforms the default docking scoring consistently and inexpensively, demonstrating that the methodology is ready for wide-scale virtual screening usage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benchmarking
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Molecular Docking Simulation*
  • Protein Conformation
  • User-Computer Interface