{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Noureldin NA"],"funding":["Ministry of Higher Education"],"pagination":["2511-2524"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8979089"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["12(4)"],"pubmed_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 <i>N</i>,<i>N</i>-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 <i>Enterococcus faecalis</i>. To further investigate the designed compounds, a homology model of <i>E. faecalis</i> 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."],"journal":["RSC advances"],"pubmed_title":["Phenylalanyl tRNA synthetase (PheRS) substrate mimics: design, synthesis, molecular dynamics and antimicrobial evaluation."],"pmcid":["PMC8979089"],"funding_grant_id":["Newton-Mosharafa fund"],"pubmed_authors":["Eladl SM","Wootton M","Noureldin NA","Richards J","Kothayer H","Baraka MM","Simons C"],"additional_accession":[]},"is_claimable":false,"name":"Phenylalanyl tRNA synthetase (PheRS) substrate mimics: design, synthesis, molecular dynamics and antimicrobial evaluation.","description":"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 <i>N</i>,<i>N</i>-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 <i>Enterococcus faecalis</i>. To further investigate the designed compounds, a homology model of <i>E. faecalis</i> 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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Jan","modification":"2024-11-20T15:49:20.022Z","creation":"2024-11-20T15:49:20.022Z"},"accession":"S-EPMC8979089","cross_references":{"pubmed":["35425259"],"doi":["10.1039/d1ra06439h"]}}