In Silico Molecular Interaction of Phenyl Alkyl Caffeine Derivatives as Monoamine Oxidase B Inhibitors Research Article
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Abstract
Background: Neurodegenerative disorders often involve increased monoamine oxidase B (MAO-B) activity, which leads to excessive reactive oxygen species (ROS) and cell damage. Neuroprotection through ROS inhibition can be achieved with MAO-B inhibitors, helping to reduce motor symptoms in Parkinson’s disease, amyloid plaques in Alzheimer’s disease, and impairment in non-motor issues such as mood, cognition, sleep, and fatigue.
Methods: This study investigated the interaction and inhibitory potential of C8-substituted phenyl alkyl caffeine derivatives against monoamine oxidase B (MAO-B) using molecular docking. Docking was performed through the Virtual Screening interface of PyRx, integrated with the AutoDock Vina engine, to evaluate binding affinity and active-site interactions. Additionally, in-silico absorption, distribution, metabolism, and excretion (ADME) profiling and drug-likeness assessments were conducted to determine their suitability as potential reversible MAO-B inhibitors.
Results: Caffeine analogs with shorter substituents (4a, 4b) showed moderate interactions with the amino acids in the substrate cavity of MAO-B, whereas derivatives with longer substituents, 8-(5-Phenylpentyl) caffeine (4d), (4e), and (4f), exhibited robust binding affinities, -10.3, -10.5, and -10.3 kcal/mol, respectively. Among these compounds, 4d emerged as the most selective inhibitor, forming strong, stable conventional hydrogen bonds. 4e and 4f also exhibited substantial binding energies. 4i displayed strong interactions with slightly lower efficacy. ADME analysis revealed 4f with high gastrointestinal (GI) absorption and blood-brain barrier (BBB) permeability, suggesting potential for CNS-targeted applications.
Conclusion: This study demonstrates that 8-(5-Phenylpentyl) caffeine (4d) and 8-(5-Phenylpentyl) caffeine (4e) are highly selective and potent inhibitors of MAO-B. Among all ligands, 8-(7-Phenylheptyl) caffeine (4f) stood out as a reversible inhibitor, having high GI and BBB permeability. These findings highlight the importance of designing selective and multifunctional MAO-B inhibitors for effective neuroprotective therapy.
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