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

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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.

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Acknowledgments

This study was funded by the Department of Biotechnology, Government of India “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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Authors and Affiliations

  1. School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601, India

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

  2. Department of Biotechnology, Manipal Institute of Technology, Manipal University, Manipal, Karnataka, 576104, India

    S. M. Fayaz

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  1. S. M. Fayaz
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  2. V. S. Suvanish Kumar
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  3. Charles K. Davis
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  4. G. K. Rajanikant
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Correspondence to G. K. Rajanikant.

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Fayaz, S.M., Suvanish Kumar, V.S., Davis, C.K. et al. Novel RIPK3 inhibitors discovered through a structure-based approach exert post-ischemic neuroprotection. Mol Divers 20, 719–728 (2016). https://doi.org/10.1007/s11030-016-9663-1

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  • DOI: https://doi.org/10.1007/s11030-016-9663-1

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