<i>In silico</i> molecular docking and molecular dynamics simulation of <i>Baeckea frutescens</i> phytochemicals as mitogen-activated protein kinase 3 (MAPK3) potential inhibitors

Molecular docking and molecular dynamics (MD) simulations were employed to evaluate Baeckea frutescens –derived compounds as potential MAPK3 inhibitors. The docking protocol was validated with an RMSD of 0.620373 Å, confirming its reliability. Docking results revealed binding affinities ranging from –5.279 to –11.77 kcal/mol, with 12 compounds exhibiting stronger affinities than –10 kcal/mol including frutescone B (42), baeckein A (69), baeckein B (70), baeckein C (71), baeckein D (72), baeckein E (73), baeckein I (77), 6- C -methylquercetin 4′- O - β -D-glucopyranoside (87), myricetin 3- O -(5′′- O -galloyl)- α -L-arabinofuranoside (90), quercetin-3- O - α -L-rhamnoside (93), 7- O -(4′,6′-digalloyl)- β -D-glucopyranosyl-5-hydroxy-2-methylchromone (108), and 6- β - C -(2′-galloylglucopyranosyl)-5,7-dihydroxy2-isopropylchromone (117). Compounds 69, 70, and 72 displayed the highest affinities, engaging in hydrogen bonding, π-sigma, and π-alkyl interactions, stabilizing the MAPK3 complex. MD simulations further confirmed their stability, with RMSD values lower than the reference system. MMGBSA (Molecular Mechanics Generalized Born Surface Area) analysis identified compound 87 as the strongest binder (ΔG bind = −60.43 kcal/mol), followed by compounds 72 and 73. ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) predictions suggested compound 42 as the most promising candidate for oral administration, while compounds 71–73 showed poor intestinal absorption but limited CNS penetration. Most compounds exhibited no genotoxicity or hepatotoxicity, though hERG II inhibition indicated potential cardiac risks. These findings provide insights into the potential of B. frutescens –derived compounds as MAPK3 inhibitors and guide future optimization for enhanced stability and pharmacokinetic properties.