Phenylalanyl tRNA synthetase (PheRS) substrate mimics: design, synthesis, molecular dynamics and antimicrobial evaluation.

Autor:	Noureldin NA; School of Pharmacy and Pharmaceutical Sciences, Cardiff University Cardiff CF10 3NB UK NANoureddine@pharmacy.zu.edu.eg.; Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University Zagazig P. C. 44519 Egypt., Richards J; Specialist Antimicrobial Chemotherapy Unit, University Hospital of Wales Heath Park Cardiff CF14 4XW UK., Kothayer H; Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University Zagazig P. C. 44519 Egypt., Baraka MM; Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University Zagazig P. C. 44519 Egypt., Eladl SM; Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University Zagazig P. C. 44519 Egypt., Wootton M; Specialist Antimicrobial Chemotherapy Unit, University Hospital of Wales Heath Park Cardiff CF14 4XW UK., Simons C; School of Pharmacy and Pharmaceutical Sciences, Cardiff University Cardiff CF10 3NB UK NANoureddine@pharmacy.zu.edu.eg.
Jazyk:	angličtina
Zdroj:	RSC advances [RSC Adv] 2022 Jan 20; Vol. 12 (4), pp. 2511-2524. Date of Electronic Publication: 2022 Jan 20 (Print Publication: 2022).
DOI:	10.1039/d1ra06439h
Abstrakt:	Antimicrobial resistance is a very challenging medical issue and identifying novel antimicrobial targets is one of the means to overcome this challenge. Phenylalanyl tRNA synthetase (PheRS) is a promising antimicrobial target owing to its unique structure and the possibility of selectivity in the design of inhibitors. Sixteen novel benzimidazole based compounds (5a-b), (6a-e), (7a-d), (9a-e) and three N , N -dimethyl-7-deazapurine based compounds (16a-c) were designed to mimic the natural substrate of PheRS, phenylalanyl adenylate (Phe-AMP), that was examined through flexible alignment. The compounds were successfully synthesised chemically in two schemes using 4 to 6-steps synthetic pathways, and evaluated against a panel of five microorganisms with the best activity observed against Enterococcus faecalis . To further investigate the designed compounds, a homology model of E. faecalis PheRS was generated, and PheRS-ligand complexes obtained through computational docking. The PheRS-ligand complexes were subjected to molecular dynamics simulations and computational binding affinity studies. As a conclusion, and using data from the computational studies compound 9e, containing the (2-naphthyl)-l-alanine and benzimidazole moieties, was identified as optimal with respect to occupancy of the active site and binding interactions within the phenylalanine and adenosine binding pockets. Competing Interests: 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. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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