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Article Dans Une Revue Journal of Computational Chemistry Année : 2022

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

Justin Overhulse
  • Fonction : Auteur
Nathan Dupper
  • Fonction : Auteur
Yanchun Guo
  • Fonction : Auteur
Boris Kashemirov
  • Fonction : Auteur
Kaiyao Wei
  • Fonction : Auteur
Carlo Petosa
Charles Mckenna

Résumé

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.

Dates et versions

hal-03806660 , version 1 (07-10-2022)

Identifiants

Citer

Yingsheng Zhou, Justin Overhulse, Nathan Dupper, Yanchun Guo, Boris Kashemirov, et al.. Toward more potent imidazopyridine inhibitors of Candida albicans Bdf1: Modeling the role of structural waters in selective ligand binding. Journal of Computational Chemistry, 2022, ⟨10.1002/jcc.26997⟩. ⟨hal-03806660⟩
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