DOI: 10.17776/csj.1860936 ISSN: 2587-2680

An Integrated In Silico Investigation of Novel MAO-B Inhibitors for Parkinson’s Disease

Arzu Öztürk Kesebir
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Monoamine oxidase-B (MAO-B) is a key enzyme involved in dopamine metabolism and plays a central role in the pathogenesis of Parkinson’s disease, making it an important pharmacological target. In this study, an integrated early-stage inhibitor discovery strategy was applied by combining ligand-based similarity screening with computational analyses to identify novel MAO-B inhibitors. Using the SwissSimilarity platform, previously reported MAO-B inhibitors were used as reference compounds, and structurally related candidates were selected and evaluated for their predicted binding potential against MAO-B. Among the screened series, compound 9 exhibited the most favorable predicted binding affinity. To assess its drug-likeness and developability, comprehensive ADMET predictions were performed, revealing an overall acceptable pharmacokinetic and toxicological profile. To clarify the molecular basis of inhibition, molecular docking analyses were carried out, demonstrating that compound 9 adopts a favorable binding orientation within the MAO-B active site and establishes key interactions with catalytically important residues. To further validate binding stability, a 100 ns molecular dynamics simulation was conducted. The MAO-B–compound 9 complex preserved its structural integrity throughout the simulation, maintaining active-site alignment and stable intermolecular interactions. Detailed analyses of RMSD, RMSF, radius of gyration, hydrogen bond occupancy, and energy profiles consistently indicated that ligand binding did not induce significant conformational disturbances in the enzyme structure. In conclusion, this study demonstrates that the integrated use of SwissSimilarity-guided compound selection and in silico modeling provides an effective strategy for the early identification of MAO-B-targeted inhibitors. Compound 9 therefore warrants further computational and experimental evaluation.

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