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

Noureldin, Nada A., Richards, Jennifer, Kothayer, Hend, Baraka, Mohammed M., Eladl, Sobhy M., Wootton, Mandy and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2022. Phenylalanyl tRNA synthetase (PheRS) substrate mimics: design, synthesis, molecular dynamics and antimicrobial evaluation. RSC Advances 12 (4) , pp. 2511-2524. 10.1039/D1RA06439H

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Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Pharmacy
Additional Information:	This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence
Publisher:	Royal Society of Chemistry
ISSN:	2046-2069
Date of First Compliant Deposit:	18 February 2022
Date of Acceptance:	5 January 2022
Last Modified:	07 May 2023 01:22
URI:	https://orca.cardiff.ac.uk/id/eprint/147633

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