Development of novel monoamine oxidase B (MAO-B) inhibitors by combined application of docking-based alignment, 3D-QSAR, ADMET prediction, molecular dynamics simulation, and MM_GBSA binding free energy.

Unsaturated ketone derivatives are known as inhibitors of monoamine oxidase B (MAO-B), a potential drug target of Parkinson's disease. Here, docking-based alignment, 3 D-QSAR (three-dimensional quantitative structure-activity relationship) studies, ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction, molecular dynamics (MD) simulation, and MM_GBSA binding free energy were performed on a novel series of MAO-B inhibitors. The objective is to predict new MAO-B inhibitors with high potency activity. The 3 D-QSAR models were created using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). Molecular docking findings indicated that compounds with strong inhibitory efficacy also had a high binding affinity. 3 D-QSAR studies showed the importance of steric, electrostatic, and H-bond acceptor fields on the inhibitory activity of MAO-B. Based on the appropriate 3 D-QSAR model, a new series of MAO-B inhibitors were predicted and their pharmacokinetic characteristics were evaluated using ADMET prediction. All screened compounds show good oral bioavailability without any side effects. Moreover, the dynamic behavior and stability of the most active compounds were evaluated using MD simulations. The results showed that unsaturated ketone derivatives are stable and compact during the 100 ns of MD simulation. Finally, the binding free energy of complexes was determined using the MM_GBSA method; the findings indicated that the T1 compound is more stable (ΔG = -409.506 KJ/mol) than the data set's highest active compound (ΔG = -31.883 KJ/mol).Communicated by Ramaswamy H. Sarma.