title: 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. Graphical Abstract A generalized workflow employed in this study. Subsequent utilization of EPS and PEPSF might lead to reduced computational time and load.
authors.affiliation: School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601, India.|Department of Biotechnology, Manipal Institute of Technology, Manipal University, Manipal, 576104, Karnataka, India.
authors.forename: S M
authors.initials: SM
authors.lastname: Fayaz
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: D015195:Drug Design; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: Dual ensemble screening (DES); Dual inhibitors; Ensemble docking; Ensemble pharmacophore; Ensemble pharmacophore-based screening (EPS); Post-EPS filtration (PEPSF)