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

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.

A generalized workflow employed in this study. Subsequent utilization of EPS and PEPSF might lead to reduced computational time and load.

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Correspondence to G. K. Rajanikant.

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This study was funded by the Department of Biotechnology, Government of India via the Bioinformatics Infrastructure Facility for Biology Teaching through Bioinformatics (BIF-BTBI) (grant number: BT/BI/25/001/2006, dated 25/03/2011).

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Fayaz, S.M., Rajanikant, G.K. Ensembling and filtering: an effective and rapid in silico multitarget drug-design strategy to identify RIPK1 and RIPK3 inhibitors. J Mol Model 21, 314 (2015). https://doi.org/10.1007/s00894-015-2855-2

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Keywords

  • Ensemble pharmacophore
  • Ensemble docking
  • Dual ensemble screening (DES)
  • Ensemble pharmacophore-based screening (EPS)
  • Post-EPS filtration (PEPSF)
  • Dual inhibitors