Computational analysis of azadirachta indica-derived phytochemicals targeting α-amylase and α-glucosidase for antidiabetic activity

• Identifies 24-methylene cycloartanol and gedunin as potent α-amylase and α-glucosidase inhibitors. • Employs molecular docking and ADMET analyses to highlight their binding and pharmacokinetic properties. • Demonstrates neem bioactives’ potential as safer, natural alternatives for diabetes treatment. • Reveals favorable drug-likeness and safety profiles, supporting further therapeutic development. • Opens pathways for clinical validation of Azadirachta indica in diabetes management. Azadirachta indica L. ( A. indica , neem), has long been used in the treatment of diabetes in numerous countries. This study aims to explore the molecular interactions of bioactive phytochemicals isolated from A. indica with two key enzymes involved in diabetes, human pancreatic α-amylase (4W93) and α-glucosidase (3CTT), using in silico approaches. Molecular docking was conducted with various ligands to evaluate their potential as inhibitors. Molecular docking analyses revealed that 24-methylene cycloartanol (24-MCL), stigmasterol (SML), and β-sitosterol (BSL) exhibited strong binding affinities (‒9.4 kcal/mol) to α-amylase, with SML forming one hydrogen bond (HB) along with multiple hydrophobic interactions. In contrast, montbretin A (MNA) showed a binding energy of ‒8.7 kcal/mol and formed several HBs. For α-glucosidase, gedunin (GN) showed the highest binding energy (‒9.1 kcal/mol), while SML exhibited a binding energy of ‒8.6 kcal/mol with one HB. Drug-likeness assessment using Lipinski’s Rule of 5 indicated that casuarine (CRE), catechin (CTN), and GN complied with the criteria without violations, while 24-MCL, SML, and BSL had one violation. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions highlighted favorable absorption profiles for 24-MCL, GN, and BSL, while MNA exhibited poor pharmacokinetic properties. Additionally, prediction of activity spectra for substances (PASS) prediction results further supported the antidiabetic potential of certain compounds. These findings warrant further in vivo and in vitro validation and clinical trials to assess 24-MCL and GN’s antidiabetic potential, while structural optimization could enhance potency for developing safer, more effective plant-based antidiabetic drugs.