Structure-based discovery and in vitro validation of inhibitors of chloride intracellular channel 4 protein.

Autor:	Olotu F; Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6139, South Africa., Medina-Carmona E; School of Biosciences, University of Kent, CT2 7NJ Canterbury, United Kingdom.; Departamento de Quimica-Fisica, Facultad de Ciencias, Universidad de Granada, Spain., Serrano-Sanchez A; School of Biosciences, University of Kent, CT2 7NJ Canterbury, United Kingdom., Ossa F; Centre for Cardiovascular Medicine and Device Innovation, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom., El-Hamdaoui A; Centre for Cardiovascular Medicine and Device Innovation, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom., Bishop ÖT; Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6139, South Africa., Ortega-Roldan JL; School of Biosciences, University of Kent, CT2 7NJ Canterbury, United Kingdom., Abdul-Salam VB; Centre for Cardiovascular Medicine and Device Innovation, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Computational and structural biotechnology journal [Comput Struct Biotechnol J] 2022 Dec 24; Vol. 21, pp. 688-701. Date of Electronic Publication: 2022 Dec 24 (Print Publication: 2023).
DOI:	10.1016/j.csbj.2022.12.040
Abstrakt:	The use of computer-aided methods have continued to propel accelerated drug discovery across various disease models, interestingly allowing the specific inhibition of pathogenic targets. Chloride Intracellular Channel Protein 4 (CLIC4) is a novel class of intracellular ion channel highly implicated in tumor and vascular biology. It regulates cell proliferation, apoptosis and angiogenesis; and is involved in multiple pathologic signaling pathways. Absence of specific inhibitors however impedes its advancement to translational research. Here, we integrate structural bioinformatics and experimental research approaches for the discovery and validation of small-molecule inhibitors of CLIC4. High-affinity allosteric binders were identified from a library of 1615 Food and Drug Administration (FDA)-approved drugs via a high-performance computing-powered blind-docking approach, resulting in the selection of amphotericin B and rapamycin. NMR assays confirmed the binding and conformational disruptive effects of both drugs while they also reversed stress-induced membrane translocation of CLIC4 and inhibited endothelial cell migration. Structural and dynamics simulation studies further revealed that the inhibitory mechanisms of these compounds were hinged on the allosteric modulation of the catalytic glutathione (GSH)-like site loop and the extended catalytic β loop which may elicit interference with the catalytic activities of CLIC4. Structure-based insights from this study provide the basis for the selective targeting of CLIC4 to treat the associated pathologies. Competing Interests: None. (Crown Copyright © 2023 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu