In Silico Design, Molecular Docking and Evaluation of a-Amylase Inhibition of Ethyl Indole-3-Carboxylate Mannich Base Derivatives as Potential Antidiabetic Agents

Author

Tamilarasi G, Archana A, Ajin T. S, Hameedhash R, Priya M, Srimathi D


Abstract

 Introduction: Type 2 diabetes mellitus (T2DM) is characterised by chronic hyperglycaemia, and inhibition of pancreatic α-amylase is an established approach to blunt postprandial glucose excursions. The indole nucleus is a privileged scaffold in medicinal chemistry, and ethyl indole-3-carboxylate Mannich bases were designed in the present work as potential α-amylase inhibitors.

Materials and Methods: Five ethyl 2-[1-(substituted amino)ethyl]-1H-indole-3-carboxylate derivatives (C-1 to C-5) were designed. Physicochemical properties, pharmacokinetic behaviour and drug-likeness were predicted with SwissADME (Lipinski, Ghose, Veber, Egan and Muegge filters), and toxicity risk with OSIRIS Property Explorer. Molecular docking was performed against human pancreatic α-amylase (PDB ID: 1B2Y) with PyRx (AutoDock Vina), and interactions were analysed in BIOVIA Discovery Studio. The in vitro α-amylase inhibitory activity was evaluated by the starch–iodine method at 10, 20, 30, 40 and 50 µg/mL, using acarbose as the standard.

Results and Discussion: All five compounds obeyed Lipinski’s rule of five with no violation (molecular weight 260.33–336.38 g/mol; consensus Log P 2.21–3.55; TPSA 45.33–71.19 Å2), were predicted to have high gastrointestinal absorption, and showed no mutagenic, tumorigenic, irritant or reproductive-toxicity risk in OSIRIS. Docking scores ranged from −7.2 to −7.9 kcal/mol, with C-3 showing the best affinity (−7.9 kcal/mol); the active-site residues Asp197, Glu233 and Asp300 of the catalytic triad, together with Gly306, Tyr62, Trp58/59, His201 and Ile235, were involved in binding. In the in vitro assay, inhibition was concentration dependent; C-1 and C-3 were the most active, giving 89.0% and 87.9% inhibition at 50 µg/mL, followed by C-2 (82.5%), C-5 (64.0%) and C-4 (36.0%).

Conclusion: The ethyl indole-3-carboxylate Mannich bases, particularly the phenylamino (C-1) and benzamido (C-3) derivatives, combine favourable drug-likeness, good predicted binding to the α-amylase active site and marked in vitro enzyme inhibition, and may be taken forward as lead molecules for antidiabetic drug development.



Keywords

α-amylase inhibition, antidiabetic activity, drug design, indole, in silico studies, Mannich bases, molecular docking, type 2 diabetes mellitus.



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References


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