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

S. M. Fayaz, V. S. Suvanish Kumar, Charles K. Davis, G. K. Rajanikant

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)719-728
Number of pages10
JournalMolecular Diversity
Volume20
Issue number3
DOIs
Publication statusPublished - 01-08-2016

Fingerprint

Receptor-Interacting Protein Serine-Threonine Kinases
Threonine
Protein Kinase Inhibitors
inhibitors
Binding Sites
Amino Acid Receptors
proteins
Proteins
Protein-Serine-Threonine Kinases
Nervous System Diseases
Computer Simulation
Necrosis
Stroke
Binding sites
Ligands
Screening
necrosis
strokes
Amino Acids
amino acids

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Information Systems
  • Molecular Biology
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Fayaz, S. M. ; Suvanish Kumar, V. S. ; Davis, Charles K. ; Rajanikant, G. K. / Novel RIPK3 inhibitors discovered through a structure-based approach exert post-ischemic neuroprotection. In: Molecular Diversity. 2016 ; Vol. 20, No. 3. pp. 719-728.
@article{22fa92a433eb4a098e2594b5ef367fbe,
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.",
author = "Fayaz, {S. M.} and {Suvanish Kumar}, {V. S.} and Davis, {Charles K.} and Rajanikant, {G. K.}",
year = "2016",
month = "8",
day = "1",
doi = "10.1007/s11030-016-9663-1",
language = "English",
volume = "20",
pages = "719--728",
journal = "Molecular Diversity",
issn = "1381-1991",
publisher = "Springer Netherlands",
number = "3",

}

Novel RIPK3 inhibitors discovered through a structure-based approach exert post-ischemic neuroprotection. / Fayaz, S. M.; Suvanish Kumar, V. S.; Davis, Charles K.; Rajanikant, G. K.

In: Molecular Diversity, Vol. 20, No. 3, 01.08.2016, p. 719-728.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel RIPK3 inhibitors discovered through a structure-based approach exert post-ischemic neuroprotection

AU - Fayaz, S. M.

AU - Suvanish Kumar, V. S.

AU - Davis, Charles K.

AU - Rajanikant, G. K.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84957965552&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84957965552&partnerID=8YFLogxK

U2 - 10.1007/s11030-016-9663-1

DO - 10.1007/s11030-016-9663-1

M3 - Article

VL - 20

SP - 719

EP - 728

JO - Molecular Diversity

JF - Molecular Diversity

SN - 1381-1991

IS - 3

ER -