Structural analysis of hERG channel blockers and the implications for drug design.

Autor: AlRawashdeh S; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada., Chandrasekaran S; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada., Barakat KH; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. Electronic address: kbarakat@ualberta.ca.
Jazyk: angličtina
Zdroj: Journal of molecular graphics & modelling [J Mol Graph Model] 2023 May; Vol. 120, pp. 108405. Date of Electronic Publication: 2023 Jan 11.
DOI: 10.1016/j.jmgm.2023.108405
Abstrakt: The repolarizing current (I kr ) produced by the hERG potassium channel forms a major component of the cardiac action potential and blocking this current by small molecule drugs can lead to life-threatening cardiotoxicity. Understanding the mechanisms of drug-mediated hERG inhibition is essential to develop a second generation of safe drugs, with minimal cardiotoxic effects. Although various computational tools and drug design guidelines have been developed to avoid binding of drugs to the hERG pore domain, there are many other aspects that are still open for investigation. This includes the use computational modelling to study the implications of hERG mutations on hERG structure and trafficking, the interactions of hERG with hERG chaperone proteins and with membrane-soluble molecules, the mechanisms of drugs that inhibit hERG trafficking and drugs that rescue hERG mutations. The plethora of available experimental data regarding all these aspects can guide the construction of much needed robust computational structural models to study these mechanisms for the rational design of safe drugs.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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