Identification of small molecule glucokinase activators for the treatment of diabetes based on plants from the traditional Chinese medicine: In silico analysis

• Published in: Microbial pathogenesis 2024-10, Vol.195, p.106851, Article 106851
• Main Authors: Khamlich, Jihane, Douiyeh, Imane, Saih, Asmae, Moussamih, Samya, Regragui, Anas, Kettani, Anass, Safi, Amal
• Format: Article
• Language: English
• Subjects: ADMET analysis; Diabetes; GKA; Glucokinase; Molecular docking analysis; Molecular dynamics analysis
• ISSN: 0882-4010; 1096-1208; 1096-1208
• DOI: 10.1016/j.micpath.2024.106851

Mutations in glucokinase (GCK) can either enhance or inhibit insulin secretion, leading to different forms of diabetes, including gestational diabetes. While many glucokinase activators (GKAs) have been explored as treatments, their long-term effectiveness has often been unsatisfactory. However, recent interest has surged with the introduction of dorzagliatin and TTP399. This study investigates the efficacy of four previously studied compounds (Swertiamarin, Apigenin, Mangiferin, and Tatanan A) in activating GCK using computational methods. Initial molecular docking revealed binding affinities ranging from −6.7 to −8.6 kcal/mol. The compounds were then evaluated for drug-likeness and pharmacokinetic properties. Re-docking studies were performed for validation. Based on their favorable binding affinities and compliance with Lipinski's rule and ADMET criteria, three compounds (Swertiamarin, Apigenin, and Tatanan A) were selected for molecular dynamics (MD) simulations. MD simulations demonstrated that Swertiamarin showed excellent stability, as indicated by analyses of RMSD, RMSF, radius of gyration (Rg), hydrogen bonding, and principal component analysis (PCA). These results suggest that Swertiamarin holds promise for further investigation in in vivo and clinical settings to evaluate its potential in enhancing GCK activity and treating diabetes. This study assessed the potential of four compounds as GCK activators using molecular docking, pharmacokinetic profiling, and MD simulations. Swertiamarin, in particular, showed significant stability and adherence to drug-likeness criteria, making it a promising candidate for further research in combating diabetes. [Display omitted] •Four compounds (Swertiamarin,Apigenin,Mangiferin and Tatanan A)were evalueted as potentiel glucokinase activators using computational techniques.•Molecular docking showed binding affinities between -6.7 and -8.6 kcal/mol, with Swertiamarin,Apigenin and Tatanan A having favorable drug-like properties.•Swertiamarin demonstrated excellent stability in molecular dynamics simulations, supported by various analyses.•These findings suggest Swertiamarin's potential for further study in treating diabetes by enhancing GCK activity.