Molecular Docking, ADME and SAR Analysis of 383 Phytochemicals in the Quest for Lead Antidiabetic Inhibitors Targeting α-Amylase and α-Glucosidase Enzymes

Abstract

Purpose: Diabetes mellitus remains a global health challenge, necessitating the exploration of safe and effective therapeutic agents. The inhibition of α-amylase and α-glucosidase enzymes plays a crucial role in controlling postprandial hyperglycemia. While synthetic inhibitors exist, they often cause gastrointestinal side effects, prompting the search for novel, naturally derived inhibitors. This study evaluates the molecular interactions of 383 phytochemicals, focusing on alkaloids, terpenes, and flavonoids, for their potential as lead antidiabetic compounds. Methods: Molecular docking studies were performed using AutoDock Vina to assess the binding affinity of selected phytochemicals against human pancreatic α-amylase (PDB ID: 5EMY) and α-glucosidase (PDB ID: 2QMJ). The physicochemical and pharmacokinetic properties of the top-performing compounds were analyzed using SwissADME, following Lipinski’s Rule of Five and Verber’s rules. Structure-activity relationship (SAR) analysis was conducted to elucidate key functional groups responsible for enzyme inhibition. Results: Flavonoids exhibited superior inhibitory potential, with binding affinities outperforming the standard inhibitor Acarbose. The most potent compounds, Amentoflavone (-9.5 kcal/mol), Hesperidin (-9.5 kcal/mol), Eriocitrin (-9.5 kcal/mol), and Diosmin (-9.4 kcal/mol), showed strong interactions with key amino acid residues. SAR analysis highlighted the significance of glycosylation and flavone / flavanol moieties in enhancing binding affinity. ADME analysis revealed favorable pharmacokinetic properties, with Amentoflavone demonstrating the highest synthetic accessibility and drug-likeness. Conclusion: This study identifies flavonoids as promising dual inhibitors of α-amylase and α-glucosidase, with Amentoflavone emerging as a lead candidate for further development as a novel antidiabetic agent, contributing to the search for safer alternatives to conventional therapies.