Chemical space navigation by machine learning models for discovering selective MAO-B enzyme inhibitors for Parkinson’s disease

Abstract

Monoamine Oxidase-B (MAO-B) is a key neuroprotective target that breaks neurotransmitters such as dopamine and releases highly reactive free radicals as the by-product. Its over-expression in the brain observed due to ageing and neurodegenerative diseases contributes to worsening neuronal degeneration. Being the primary enzyme for dopamine metabolism in the substantia nigra of the brain and due to the lack of efficient drug candidates, MAO-B selective, reversible inhibition is hot topic of research in Parkinson’s disease (PD). This study developed machine learning (ML) models that predict the activity of experimentally tested indole and indazole derivatives against MAO-B using linear genetic function approximation (GFA) and two non-linear support vector machine (SVM) and artificial neural network (ANN) techniques. ANN model with an R² of 0.9704 for the training dataset, $q^2$of 0.9436 for cross-validation and $r^2$of 0.9025 for the test dataset were identified as the best-performing ML model with the seven significant molecular descriptors CATS2D_04_DA, CATS2D_05_DA, CATS3D_06_LL, Mor04u, Mor25m, P_VSA_v_2 and nO. The robust ML model was then employed to design novel MAO-B inhibitors with similar core scaffolds and their biological activity prediction. ANN model was further employed in the virtual screening of 4356 molecules from the ChEMBL database. Applicability domain analysis and pharmacokinetic and toxicity profiles predicted three newly designed molecules (22 N, 23 N and 24 N) and two virtually screened best ChEMBL molecules as potential drug candidates using the ANN ML model. Molecular docking studies of the best-identified compounds were performed to understand the molecular mechanism of interactions having high binding energy and selectivity with the MAO-B enzyme. The current study shortlisted 5 potential lead compounds as potent and selective MAO-B inhibitors, which could further be carried forward for in vitro and in vivo studies to discover small molecules against neurodegenerative disease.