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 IC50 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.