Discovery of Novel Pim-1 Kinase Inhibitors with a Flexible-Receptor Docking Protocol

J Chem Inf Model. 2019 Oct 28;59(10):4116-4119. doi: 10.1021/acs.jcim.9b00494. Epub 2019 Oct 17.

Abstract

A flexible-receptor docking protocol was designed for treating binding-site side-chain flexibility by integrating essential aspects of "Conformational Selection" and "Induced Fit" in a hierarchical fashion. Assessed in a diverse set of pharmaceutically relevant targets, this protocol showed improved performance in reproducing binding poses and ligand enrichment studies compared to rigid-receptor docking. Moreover, it has also exhibited encouraging efficiency in prospective ligand discovery for Pim-1 kinase, which led to novel Pim-1 inhibitors with single-digit nanomolar potencies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Drug Discovery*
  • Models, Molecular
  • Molecular Dynamics Simulation*
  • Protein Conformation
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*

Substances

  • Proto-Oncogene Proteins c-pim-1