title: Novel RIPK3 inhibitors discovered through a structure-based approach exert post-ischemic neuroprotection.
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.
authors.affiliation: School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601, India.|Department of Biotechnology, Manipal Institute of Technology, Manipal University, Manipal, Karnataka, 576104, India.
authors.forename: S M
authors.initials: SM
authors.lastname: Fayaz
authors.affiliation: School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601, India.
authors.forename: V S
authors.initials: VS
authors.lastname: Suvanish Kumar
authors.affiliation: School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601, India.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Davis
authors.affiliation: School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601, India. rajanikant@nitc.ac.in.
authors.forename: G K
authors.initials: GK
authors.lastname: Rajanikant
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D006801:Humans; D062105:Molecular Docking Simulation; D000066829:Neuroprotection; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: Dual ensemble screening (DES); Ischemic stroke; Necroptosis; Post-ischemic neuroprotection