Novel RIPK3 inhibitors discovered through a structure-based approach exert post-ischemic neuroprotection
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...
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| Veröffentlicht in: | Molecular diversity 2016-08, Vol.20 (3), p.719-728 |
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| container_title | Molecular diversity |
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| creator | Fayaz, S. M. Suvanish Kumar, V. S. Davis, Charles K. Rajanikant, G. K. |
| description | 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. |
| doi_str_mv | 10.1007/s11030-016-9663-1 |
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| subjects | Binding Sites - drug effects Biochemistry Biomedical and Life Sciences Cell Line Cell Survival - drug effects Chemical compounds Computer Simulation Humans Inhibitor drugs Life Sciences Molecular Docking Simulation Neuroprotection Organic Chemistry Original Article Pharmaceutical sciences Pharmacy Polymer Sciences Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors Receptor-Interacting Protein Serine-Threonine Kinases - chemistry Stroke Structure-Activity Relationship |
| title | Novel RIPK3 inhibitors discovered through a structure-based approach exert post-ischemic neuroprotection |
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