Rapid flexible docking using a stochastic rotamer library of ligands

Feng Ding, Shuangye Yin, Nikolay V. Dokholyan

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Existing flexible docking approaches model the ligand and receptor flexibility either separately or in a loosely coupled manner, which captures the conformational changes inefficiently. Here, we propose a flexible docking approach, MedusaDock, which models both ligand and receptor flexibility simultaneously with sets of discrete rotamers. We developed an algorithm to build the ligand rotamer library "on-the-fly" during docking simulations. MedusaDock benchmarks demonstrate a rapid sampling efficiency and high prediction accuracy in both self- (to the cocrystallized state) and cross-docking (to a state cocrystallized with a different ligand), the latter of which mimics the virtual screening procedure in computational drug discovery. We also perform a virtual screening test of four flexible kinase targets, including cyclin-dependent kinase 2, vascular endothelial growth factor receptor 2, HIV reverse transcriptase, and HIV protease. We find significant improvements of virtual screening enrichments when compared to rigid-receptor methods. The predictive power of MedusaDock in cross-docking and preliminary virtual-screening benchmarks highlights the importance to model both ligand and receptor flexibility simultaneously in computational docking.

Original languageEnglish (US)
Pages (from-to)1623-1632
Number of pages10
JournalJournal of Chemical Information and Modeling
Volume50
Issue number9
DOIs
StatePublished - Sep 27 2010

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

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