Identification of Novel Inhibitors Targeting Membrane-Bound MAO-B and COMT: A Molecular Docking and Dynamics Study

Monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are key enzymes involved in the metabolism of neurotransmitters, and their dysregulation is closely associated with the pathophysiology of Parkinson's disease. While soluble forms of these enzymes have been extensively studied, membrane-bound variants are increasingly recognized as more physiologically relevant targets for therapeutic intervention, due to their localization in the central nervous system and influence on synaptic neurotransmitter levels. Therefore, in this study, we aimed to identify novel peptide inhibitors specifically targeting membrane-bound MAO-B and COMT. A large library of peptides was designed with constraints to facilitate blood–brain barrier (BBB) permeability, including hydrophobicity index, net charge, and peptide length. Prior to docking, MAO-B was modeled within an outer mitochondrial membrane (OMM) model, while COMT within an endoplasmic reticulum (ER) model, to capture their biologically relevant anchoring environments, and account for the structural and electrostatic effects of lipid bilayers. A combination of molecular docking and molecular dynamics simulations was employed to screen peptides for binding affinity, structural stability, and key interactions with the enzyme active sites. Docking results revealed several candidate peptides forming stable hydrogen bonds and engaging critical residues at the enzyme active sites. Molecular dynamics simulations confirmed the stability of these peptide–enzyme complexes and highlighted interactions crucial for inhibitory potential. Overall, these findings provide molecular-level insights into the design of peptide inhibitors against membrane-bound enzymes, offering promising leads for the development of novel therapeutics for Parkinson's disease.