Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations

Bioorg Med Chem. 2016 Apr 15;24(8):1683-95. doi: 10.1016/j.bmc.2016.02.040. Epub 2016 Mar 2.

Abstract

Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50=143 nM and 68 nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity.

Keywords: 2-Oxoamides; Docking; Inhibitors; Molecular dynamics; Secreted phospholipase A(2).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Group II Phospholipases A2 / antagonists & inhibitors*
  • Group II Phospholipases A2 / metabolism*
  • Humans
  • Kinetics
  • Mice
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Phospholipase A2 Inhibitors / chemical synthesis
  • Phospholipase A2 Inhibitors / chemistry
  • Phospholipase A2 Inhibitors / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Phospholipase A2 Inhibitors
  • Pyridines
  • oxoamide
  • Group II Phospholipases A2