Computational studies on the cholinesterase, beta-secretase 1 (BACE1) and monoamine oxidase (MAO) inhibitory activities of endophytes-derived compounds: towards discovery of novel neurotherapeutics.

Cholinesterases, beta-secretase 1 (BACE1) and monoamine oxidase (MAO) are significant in the etiology of neurodegenerative diseases. Inhibition of these enzymes is therefore a major strategy for the development of neurotherapeutics. Even though, this strategy has birthed some approved synthetic drugs, they are characterized by adverse effects. It is therefore, imperative to explore promising alternatives. Consequently, we assessed the inhibitory activities of some endophytes-derived compounds against selected targets towards discovery of novel neurotherapeutics. Standard inhibitors and 83 endophytes-derived compounds were docked against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), BACE 1 and MAO using AutodockVina while the molecular interactions between the selected targets and the compounds with notable binding affinity were viewed through Discovery Studio Visualizer. Druglikeness and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) and blood brain barrier (BBB) properties of the top 4 compounds were evaluated using the Swiss online ADME web tool and OSIRIS server; ligands-enzymes complex stability was assessed through molecular dynamics (MD) simulation. From the 83 compounds, asperflavin, ascomfurans C, camptothecine and corynesidone A exhibited remarkable inhibitory activity against all the four target enzymes compared to the respective standard inhibitors. However, only corynesidone A could transverse the BBB and predicted to be safe. MD simulation of the unbound and complexed enzymes with corynesidone A showed that the complexes were stable throughout the simulation time. Given the exceptional inhibitory activity of endophytes-derived corynesidone A against the four selected targets, its ability to permeate the BBB, excellent drugability properties as well as its stability when complexed with the enzymes, it is a good candidate for further studies towards development of new neurotherapeutics.Communicated by Ramaswamy H. Sarma.