Novel Flavonols from Macaranga Inermis as Promising Mpro Inhibitors: A Quantum Mechanical and In Silico Investigation for Pan-Coronavirus Targeting

Flavonoids, a vital class of phytochemicals, are known for their diverse pharmacological activities, including potent antiviral effects. This study evaluates two newly reported flavonols, macainermisin A and macainermisin B, as potential inhibitors of the main protease (M^pro) across multiple coronavirus variants using an integrated in silico approach comprising DFT calculations, molecular docking, ADMET/drug-likeness profiling, and 100 ns molecular dynamics simulations. Docking studies revealed that macainermisin A exhibited binding affinities ranging from −7.5 to −8.6 kcal/mol, while macainermisin B showed even stronger binding, with a highest affinity of −8.5 kcal/mol against M^pro from SARS-CoV-2 (PDB ID: 8HVK). DFT analysis confirmed structural stability across gas and solvent phases, with negligible geometric distortions. However, chemical reactivity descriptors (e.g., HOMO–LUMO gap, electrophilicity index) varied significantly with solvent polarity, indicating favorable energetic adaptation. ADMET profiling showed high gastrointestinal absorption (>90%), non-hepatotoxicity, no CYP2D6 inhibition, and an acceptable logP value of macainermisin B, supporting good oral bioavailability. Drug-likeness filters (Lipinski, Veber, and Ghose rules) were satisfied for both compounds. Molecular dynamics simulations confirmed the stability of the M^pro–macainermisin A complex (8HOL) over 100 ns, with low RMSD (<3.5 Å), stable hydrogen bonding, and consistent radius of gyration. Collectively, these findings position macainermisins A and B as promising antiviral candidates targeting coronavirus M^pro, warranting further experimental validation.