The impact of binding site waters on the activity/selectivity trade-off of Janus kinase 2 (JAK2) inhibitors

Bioorg Med Chem. 2019 Apr 15;27(8):1497-1508. doi: 10.1016/j.bmc.2019.02.029. Epub 2019 Feb 16.

Abstract

Structure based optimization of B39, an indazole-based low micromolar JAK2 virtual screening hit is reported. Analysing the effect of certain modifications on the activity and selectivity of the analogues suggested that these parameters are influenced by water molecules available in the binding site. Simulation of water networks in combination with docking enabled us to identify the key waters and to optimize our primary hit into a low nanomolar JAK2 lead with promising selectivity over JAK1.

Keywords: ATP site; Activity; Indazole; Inhibitor; Janus kinase JAK2; Selectivity; Water network.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Drug Design
  • Humans
  • Indazoles / chemistry*
  • Indazoles / pharmacology*
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 1 / chemistry
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / chemistry
  • Janus Kinase 2 / metabolism
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Indazoles
  • Protein Kinase Inhibitors
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2