Molecular Docking, Pharmacophore Modeling, 3D QSAR, Molecular Dynamics Simulation and MMPBSA Studies on Hydrazine-Linked Thiazole Analogues as MAO-B Inhibitors

Background: Monoamine oxidase-B (MAO-B) is crucial in breaking down biogenic and dietary amines, with its dysregulation linked to Parkinson’s disease. Objective: This study aims to explore the MAO-B inhibitory potential of 34 hydrazine-linked thiazole derivatives through computational techniques. Methods: Molecular docking against MAO-B (2BYB) assessed binding affinity, complemented by MMGBSA for binding energy evaluation. Pharmacophore modeling and QSAR analysis identified structural features essential for inhibition, while molecular dynamics (MD) simulations validated the stability of ligand-MAO-B complexes. Results: Compound T18 exhibited outstanding binding affinity, while T9 showed the lowest. In vitro studies revealed that T2 had the weakest inhibitory potential, while T19 demonstrated the highest. Pharmacophore modeling identified the six-feature hypothesis ADHRRR_1 as the key structural feature for optimal inhibition. QSAR analysis provided insight into the importance of pharmacophoric features, including the electron-deficient 3-pyridine at N1 of hydrazine, which acts as an electron-withdrawing group that enhances interactions with the enzyme active site, making pyridine a valuable pharmacophore. Additionally, the electronegative fluorinated phenyl ring at C4 of thiazole enhances blood-brain barrier (BBB) permeability and selectivity for MAO-B. Notably, the methyl group on T19 acted as a hydrophobic feature, increasing electron density and boosting inhibitory activity. MD simulations confirmed the stability of the T18/2BYB and T19/2BYB complexes. Furthermore, T19 displayed superior CNS activity and BBB permeability, confirming the methyl group as crucial for enhanced action. Conclusion: These findings underscore the potential of hydrazine-linked thiazole derivatives as potent MAO-B inhibitors. Future in vivo studies are essential to explore their therapeutic benefits further.