Novel RIPK3 inhibitors discovered through a structure-based approach exert post-ischemic neuroprotection

Mol Divers. 2016 Aug;20(3):719-28. doi: 10.1007/s11030-016-9663-1. Epub 2016 Feb 12.

Abstract

Necroptosis or programmed necrosis is evident in various neurological disorders such as ischemic stroke. Receptor interacting serine/threonine protein kinase 3 (RIPK3) is one of the crucial targets of necroptosis and inhibition of this protein exerts neuroprotection. However, knowledge regarding the three-dimensional structure and binding site information of this protein is lacking. In the present study, structure-based in silico methods were implemented to identify the key amino acids in the RIPK3 binding site that might be responsible for ligand interactions. Further, novel RIPK3 inhibitors were identified through a dual ensemble screening strategy. Three inhibitors exhibited binding to RIPK3 in micromolar concentrations and exerted post-ischemic neuroprotection in vitro.

Keywords: Dual ensemble screening (DES); Ischemic stroke; Necroptosis; Post-ischemic neuroprotection.

MeSH terms

  • Binding Sites / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Computer Simulation
  • Humans
  • Molecular Docking Simulation
  • Neuroprotection
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Receptor-Interacting Protein Serine-Threonine Kinases / chemistry
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases