Toward more potent imidazopyridine inhibitors of Candida albicans Bdf1: Modeling the role of structural waters in selective ligand binding
| Autor: | Yingsheng Zhou, Justin M. Overhulse, Nathan J. Dupper, Yanchun Guo, Boris A. Kashemirov, Kaiyao Wei, Jérôme Govin, Carlo Petosa, Charles E. McKenna |
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| Přispěvatelé: | Department of Chemistry, University of Southern California (USC), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA) |
| Rok vydání: | 2022 |
| Předmět: |
BET inhibition
Binding Sites receptor-binding model structural water General Chemistry Ligands molecular dynamics Computational Mathematics [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases Candida albicans Humans antifungal drugs bromodomains [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Transcription Factors |
| Zdroj: | Journal of Computational Chemistry Journal of Computational Chemistry, 2022, ⟨10.1002/jcc.26997⟩ |
| ISSN: | 1096-987X 0192-8651 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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