Toward more potent imidazopyridine inhibitors of Candida albicans Bdf1 Modeling the role of structural waters in selective ligand binding

Toward more potent imidazopyridine inhibitors of Candida albicans Bdf1 : Modeling the role of structural waters in selective ligand binding

© 2022 The Authors. Journal of Computational Chemistry published by Wiley Periodicals LLC.

Bibliographische Detailangaben
Veröffentlicht in:Journal of computational chemistry. - 1984. - 43(2022), 32 vom: 15. Dez., Seite 2121-2130
1. Verfasser: Zhou, Yingsheng (VerfasserIn)
Weitere Verfasser: Overhulse, Justin M, Dupper, Nathan J, Guo, Yanchun, Kashemirov, Boris A, Wei, Kaiyao, Govin, Jérôme, Petosa, Carlo, McKenna, Charles E
Format: Online-Aufsatz
Sprache:English
Veröffentlicht: 2022
Zugriff auf das übergeordnete Werk:Journal of computational chemistry
Schlagworte:Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't BET inhibition Candida albicans antifungal drugs bromodomains molecular dynamics receptor-binding model structural water mehr... imidazopyridine Ligands Transcription Factors
Beschreibung
Zusammenfassung:© 2022 The Authors. Journal of Computational Chemistry published by Wiley Periodicals LLC.
Novel agents to treat invasive fungal infections are urgently needed because the small number of established targets in pathogenic fungi makes the existing drug repertoire particularly vulnerable to the emergence of resistant strains. Recently, we reported that Candida albicans Bdf1, a bromodomain and extra-terminal domain (BET) bromodomain with paired acetyl-lysine (AcK) binding sites (BD1 and BD2) is essential for fungal cell growth and that an imidazopyridine (1) binds to BD2 with selectivity versus both BD1 and human BET bromodomains. Bromodomain binding pockets contain a conserved array of structural waters. Molecular dynamics simulations now reveal that one water molecule is less tightly bound to BD2 than to BD1, explaining the site selectivity of 1. This insight is useful in the performance of ligand docking studies to guide design of more effective Bdf1 inhibitors, as illustrated by the design of 10 new imidazopyridine BD2 ligands 1a-j, for which experimental binding and site selectivity data are presented
Beschreibung:Date Completed 14.11.2022
Date Revised 10.09.2024
published: Print-Electronic
Citation Status MEDLINE
ISSN:1096-987X
DOI:10.1002/jcc.26997