Computational Screening of Selected Bioactive Phytochemicals Against α-Amylase with Drug-Likeness Evaluation

• EGCG showed the strongest α-amylase binding affinity among all studied phytochemicals • Naringenin and Kaempferol demonstrated high docking values and stable active-site binding • Most tested phytochemicals complied with Lipinski’s rules, indicating good drug-likenes • ADMET predictions revealed high gastrointestinal absorption for five screened compounds Type 2 diabetes mellitus (T2DM) remains a worldwide metabolic disorder characterized by elevated blood sugar levels over a long period coming from the compromised secretion of insulin. One of the critical strategies that can be employed to control blood glucose levels after meals is the inhibition of enzymes responsible for the hydrolysis of carbohydrates such as, α-amylase. In this research, we investigated the potential of certain phytochemicals in the inhibition of α-amylase by performing in silico molecular docking studies and pharmacokinetic evaluations. Eight phytochemicals, namely Myricetin, Naringenin, Quercetin, Kaempferol, Epigallocatechin gallate (EGCG), Curcumin, Rosmarinic acid, and Ferulic acid, were assessed alongside the reference drug Acarbose. Swiss Model was used to build the 3D structure of α-amylase (Sequence ID: NP₀01373038. 1; sequence coverage: 1-511; total score: 2749). Most phytochemicals were drug likeness according to screening for Lipinski’s Rule of Five, having molecular weights between 194. 18 and 368. 38 g/mol, and logP values between -1. 58 and 3. 03. Analysis of ADMET properties showed that five compounds have rather good gastrointestinal (GI) absorption. Docking results shown a strong binding affinity of the ligands with the receptor, where EGCG had the highest binding energy of -9. 6 kcal/mol, and Naringenin and Kaempferol both had a binding energy of -9. 1 kcal/mol. Key hydrogen bond interactions were identified with active site residues, such as Arg306 and Ser18 (EGCG), and Asp315 and Gln78 (Naringenin and Kaempferol). In contrast, Acarbose showed a lower binding affinity of -6. 9 kcal/mol. The BOILED-Egg and bioavailability radar models confirmed favorable intestinal absorption for most compounds and non-substrate behavior for P-glycoprotein. Overall, this study highlights EGCG, Naringenin, and Kaempferol as promising natural α-amylase inhibitors with favorable pharmacokinetic properties.