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A multilevel theoretical study to disclose the binding mechanisms of gold(III) bipyridyl compounds as selective aquaglyceroporin inhibitors

Graziani, Valentina, Marrone, Alessandro, Re, Nazzareno, Coletti, Cecilia, Platts, James A. and Casini, Angela 2017. A multilevel theoretical study to disclose the binding mechanisms of gold(III) bipyridyl compounds as selective aquaglyceroporin inhibitors. Chemistry - a European Journal 23 (55) , pp. 13802-13813. 10.1002/chem.201703092

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Abstract

Structural studies have paved the avenue to a deeper understanding of aquaporins (AQPs), small ancient proteins providing efficient transmembrane pathways for water, small uncharged solutes such as glycerol, and possibly gas molecules. Despite the numerous studies, their roles in health and disease remain to be fully disclosed. The recent discovery of AuIII complexes as potent and selective inhibitors of aquaglyceroporin isoforms paves the way to their possible therapeutic application. The binding of the selective human AQP3 inhibitor, the cationic complex [Au(bipy)Cl2]+ (Aubipy), to the protein channel has been investigated here by means of a multi-level theoretical workflow that includes QM, MD and QM/MM approaches. The hydroxo complex was identified as the prevalent form of Aubipy in physiological media and its binding to AQP3 studied by MD. Both non-covalent and coordinative Aubipy–AQP3 adducts were simulated to probe their role in the modulation of water channel functionality. The electronic structures of representative Aubipy–AQP3 adducts were then analysed to unveil the role played by the metal moiety in their stabilisation. This study spotlights the overall importance of three key aspects for AQP3 inhibition: 1) water speciation of the AuIII complex, 2) stability of non-covalent adducts and 3) conformational changes induced within the pore by the coordinative binding of AuIII. The obtained results are expected to orient future developments in the design of isoform-selective AuIII inhibitors.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
Chemistry
Publisher: WileyBlackwell
ISSN: 0947-6539
Date of First Compliant Deposit: 9 August 2017
Date of Acceptance: 1 August 2017
Last Modified: 25 Feb 2019 22:53
URI: http://orca.cf.ac.uk/id/eprint/103445

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