Ensembling and filtering

an effective and rapid in silico multitarget drug-design strategy to identify RIPK1 and RIPK3 inhibitors

S. M. Fayaz, G. K. Rajanikant

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Necroptosis, a programmed necrosis pathway, is witnessed in diverse human diseases and is primarily regulated by receptor-interacting serine/threonine protein kinase 1 (RIPK1) and RIPK3. Ablation or inhibition of these individual proteins, or both, has been shown to be protective in various in vitro and in vivo disease models involving necroptosis. In this study, we propose an effective and rapid virtual screening strategy to identify multitarget inhibitors of both RIPK1 and RIPK3. It involves ensemble pharmacophore-based screening (EPS) of a compound database, post-EPS filtration (PEPSF) of the ligand hits, and multiple dockings. Structurally diverse inhibitors were identified through ensemble pharmacophore features, and the speed of this process was enhanced by filtering out the compounds containing cross-features. The stability of these inhibitors with both of the proteins was verified by means of molecular dynamics (MD) simulation. [Figure not available: see fulltext.]

Original languageEnglish
Article number314
Pages (from-to)1-13
Number of pages13
JournalJournal of Molecular Modeling
Volume21
Issue number12
DOIs
Publication statusPublished - 01-12-2015

Fingerprint

Receptor-Interacting Protein Serine-Threonine Kinases
inhibitors
Screening
drugs
proteins
Proteins
screening
Pharmaceutical Preparations
Ablation
Molecular dynamics
necrosis
ablation
Ligands
Computer simulation
molecular dynamics
ligands
simulation

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Computational Theory and Mathematics
  • Inorganic Chemistry

Cite this

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abstract = "Necroptosis, a programmed necrosis pathway, is witnessed in diverse human diseases and is primarily regulated by receptor-interacting serine/threonine protein kinase 1 (RIPK1) and RIPK3. Ablation or inhibition of these individual proteins, or both, has been shown to be protective in various in vitro and in vivo disease models involving necroptosis. In this study, we propose an effective and rapid virtual screening strategy to identify multitarget inhibitors of both RIPK1 and RIPK3. It involves ensemble pharmacophore-based screening (EPS) of a compound database, post-EPS filtration (PEPSF) of the ligand hits, and multiple dockings. Structurally diverse inhibitors were identified through ensemble pharmacophore features, and the speed of this process was enhanced by filtering out the compounds containing cross-features. The stability of these inhibitors with both of the proteins was verified by means of molecular dynamics (MD) simulation. [Figure not available: see fulltext.]",
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Ensembling and filtering : an effective and rapid in silico multitarget drug-design strategy to identify RIPK1 and RIPK3 inhibitors. / Fayaz, S. M.; Rajanikant, G. K.

In: Journal of Molecular Modeling, Vol. 21, No. 12, 314, 01.12.2015, p. 1-13.

Research output: Contribution to journalArticle

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