From quantum chemistry to dynamics: Computational insights into Petrosin as a promising antidiabetic α-amylase inhibitor

The search for novel antidiabetic agents has sparked interest in natural compounds with α-amylase inhibitory potential. This study comprehensively evaluated Petrosin through toxicity, pharmacokinetic, quantum chemical, docking, and molecular dynamics analyses. Toxicity profiling indicated that Petrosin is non-mutagenic, non-carcinogenic, and safer than Acarbose, Miglitol, and Voglibose. Cardiotoxicity assessment revealed no significant risk of hERG inhibition, supporting cardiovascular safety. ADMET predictions demonstrated high intestinal absorption, favorable distribution, and efficient clearance, indicating its potential as a systemically acting inhibitor. Density functional theory (DFT) calculations revealed a narrow HOMO-LUMO gap, moderate electrophilicity, and a balanced hardness/softness profile, indicating favorable electronic adaptability relevant to intermolecular interactions. Thermodynamic descriptors suggested a structurally robust molecular framework, while subsequent docking and molecular dynamics analyses supported its stable binding behavior and potential bioactivity. Docking studies revealed a strong binding affinity (-10.4 kcal/mol) with α-amylase, driven by hydrogen bonds, hydrophobic, and electrostatic interactions. Molecular dynamics simulations confirmed the complex's stability, with key residues (ASP197, THR163, TYR62) showing low fluctuations and persistent binding. MM/GBSA analysis indicated a binding affinity for Petrosin (ΔG_total = −35.13 ± 3.56 kcal/mol), suggesting its viability as a lead inhibitor. Petrosin’s interactions with key residues point to a stable and promising binding mode for further optimization. These findings highlight Petrosin as a safe, stable, and potent systemic α-amylase inhibitor, providing strong computational support for its progression in antidiabetic drug development.