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Phenylalanyl tRNA synthetase (PheRS) substrate mimics: design, synthesis, molecular dynamics and antimicrobial evaluation
Faculty
Pharmacy
Year:
2022
Type of Publication:
ZU Hosted
Pages:
Authors:
Mohammed Mohamed Mahmoud Baraka
Staff Zu Site
Abstract In Staff Site
Journal:
RSC Advances Royal Society of Chemistry
Volume:
Keywords :
Phenylalanyl tRNA synthetase (PheRS) substrate mimics:
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.
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Abdallah Ahmed Abdallah Elshanawany, "Development and validation of liquid chromatographic method for simultaneous determination of amiloride hydrochloride and hydrochlorothiazide in human urine", لايوجد, 1900
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