Structure-based discovery and in vitro validation of inhibitors of chloride intracellular channel 4 protein
Metadata
Show full item recordEditorial
Elsevier
Materia
Chloride intracellular channel protein 4 GSH-like catalytic site Structure-based drug discovery Computational high-throughput screening Nuclear magnetic resonance Allosteric inhibition
Date
2022-12-24Referencia bibliográfica
F. Olotu, E. Medina-Carmona, A. Serrano-Sanchez et al. Structure-based discovery and in vitro validation of inhibitors of chloride intracellular channel 4 protein. Computational and Structural Biotechnology Journal 21 (2023) 688–701 [https://doi.org/10.1016/j.csbj.2022.12.040]
Abstract
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. Structurebased
insights from this study provide the basis for the selective targeting of CLIC4 to treat the associated
pathologies.