QSAR Modelling of Novel Coumarin Derivatives for MAO-B Inhibition

We report here the design of new inhibitors against human monoamine oxidase (hMAO-B) as potential treatment of Parkinson’s disease. We have completed computer-aided molecular design of MAO-B inhibitors by In situ modification of the reference crystal structure of 7-(3-chlorobenzyloxy)-4-(methylamino) methyl-coumarin cocrystallized (COU1) in complex with MAO-B (Protein Data Bank (PDB) entry code: 2v61) using MM-PB approach. A QSAR model built for a training set of 29 COUs with reported inhibitory activities (IC50exp) displayed a significant correlation between the computed relative Gibbs free energies (rGFE, ∆∆Gcom) of MAO-B – inhibitor complex formation and IC50exp (pIC50exp = -0.22.∆∆Gcom +7.73; R2 = 0.93). With this QSAR model we were able to explain almost 93% of the variation of observed inhibition data. The predictive capability of the QSAR model was validate by generating the 3D QSAR MAO-B inhibition Pharmacophore (PH4) the estimated IC50pred of which displayed a non-less significant correlation with the observed IC50exp (R2 = 0.91) making this PH4 a reliable chemical space virtual screening tool. Deep analysis of MAO-B – inhibitor interactions at the enzyme active site suggested structural information about interesting building blocks for enumerating a large and diverse virtual combinatorial library (VCL) of 67,949 analogues of the reference inhibitor (COU1). The best PH4 mapping hit emerging from the virtual screening displays a half-maximal inhibitory concentration of 20 pM. Combining molecular modeling and PH4 model resulted in proposed novel potent anti-Parkinson’s agent candidates with favorable pharmacokinetic profiles. Despite the lack of Molecular Dynamics (MD) check of the conformational stability of novel predicted potent analogues, the resulting PH4, as virtual screening tool, can help processing larger databases in search of coumarin scaffold bearing MAO-B inhibitors.