Flavokawain A: A Natural MAO‐A Inhibitor With Therapeutic Promise for Depression

Flavokawain A, a naturally occurring chalcone derived from Piper methysticum , has been explored for its neurotherapeutic potential. This study investigates the inhibitory activity of flavokawain A against both MAO‐A and MAO‐B isoforms using a comprehensive approach that integrates in vitro enzyme assays with in silico modelling techniques. Flavokawain A exhibited potent and selective inhibition of MAO‐A, with an IC 50 value of 0.077 µM and a moderate selectivity index of 4.84, as compared to the clinically used reversible MAO‐A inhibitor toloxatone. Blood–brain barrier permeability, assessed via parallel artificial membrane permeability assay, confirmed flavokawain A's central nervous system (CNS) drug‐likeness. Molecular docking and dynamics simulations revealed strong and stable binding of flavokawain A within the MAO‐A active site, supported by key hydrogen bonds and hydrophobic interactions, particularly involving Tyr444 and Lys305. Post‐dynamic analyses, including principal component analysis (PCA), dynamic cross‐correlation matrix (DCCM), and free energy landscape (FEL) mapping, indicated greater conformational adaptability and domain cooperativity in MAO‐A compared to MAO‐B. Quantum chemical (density functional theory) analysis further validated the reactivity and binding potential of flavokawain A. Collectively, these findings position flavokawain A as a promising natural, CNS‐permeant lead compound with selective MAO‐A inhibitory activity, supporting its further development for the treatment of depression and related neuropsychiatric disorders.