Biochemical and computational inhibition of α-glucosidase by novel metronidazole-linked 1H-1,2,3-triazole and carboxylate moieties: kinetics and dynamic investigations

• Published in: Journal of biomolecular structure & dynamics 2024-03, p.1-21
• Main Authors: Ullah, Saeed, Halim, Sobia Ahsan, Waqas, Muhammad, Mansoor, Farheen, Avula, Satya Kumar, Khan, Farhan A, Perviaz, Muhammad, Ogaly, Hanan A, Khan, Ajmal, Al-Harrasi, Ahmed
• Format: Article
• Language: English
• ISSN: 1538-0254
• DOI: 10.1080/07391102.2024.2322622

In the current study, metronidazole derivatives containing 1H-1,2,3-triazole and carboxylate moieties were evaluated in vitro and by computational methods for their anti-diabetic potential to insight into their medicinal use for the management of type II diabetes mellitus. Interestingly all 14 compounds displayed high to significant inhibitory capability against the key carbohydrate's digestive enzyme α-glucosidase with IC50 values in range of 9.73-56.39 μM, as compared to marketed drug acarbose (IC50 = 873.34 ± 1.67 μM). Compounds 5i and 7c exhibited the highest inhibition, therefore, these two compounds were further evaluated for their mechanistic studies to explore its type of inhibition. Compounds 5i and 7c both displayed a concentration-dependent (competitive type of inhibition) with Ki values 7.14 ± 0.01, 6.15 ± 0.02 μM, respectively, which conclude their favourable interactions with the active site residues of the α-glucosidase. Interestingly all compounds are non-cytotoxic against BJ cell line. To further validate our findings, in-silico approaches like molecular docking, and molecular dynamic simulations were applied to investigate the mode of bindings of compounds with the enzyme and identifies their inhibition mechanism, which strongly complements our experimental findings.Communicated by Ramaswamy H. Sarma.