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胆碱酯酶（cholinesterases）、β-分泌酶1（beta-secretase 1, BACE1）以及单胺氧化酶（monoamine oxidase, MAO）在神经退行性疾病的病因学中具有关键作用。因此，抑制这类酶类是开发神经治疗药物的核心策略。尽管该策略已催生多款获批的合成类药物，但这类药物往往伴随不良反应，因此探索具有潜力的替代疗法迫在眉睫。为此，本研究评估了若干内生菌来源的化合物对选定靶点的抑制活性，以期发现新型神经治疗药物。研究采用AutodockVina工具，将标准抑制剂与83种内生菌来源的化合物分别与乙酰胆碱酯酶（acetylcholinesterase, AChE）、丁酰胆碱酯酶（butyrylcholinesterase, BChE）、BACE1以及MAO进行分子对接；同时借助Discovery Studio Visualizer可视化工具，观察选定靶点与结合亲和力优异的化合物之间的分子相互作用。本研究通过Swiss在线ADME网络工具与OSIRIS服务器，对排名前四的化合物的药物相似性、ADMET（吸收-分布-代谢-排泄-毒性）以及血脑屏障（blood brain barrier, BBB）穿透特性进行评估；并通过分子动力学（molecular dynamics, MD）模拟评估配体-酶复合物的稳定性。在83种受试化合物中，曲黄素（asperflavin）、子囊呋喃素C（ascomfurans C）、喜树碱（camptothecine）以及棒状菌素A（corynesidone A）相较于各自的标准抑制剂，对四种靶点酶均表现出显著的抑制活性。然而，仅有棒状菌素A能够穿透血脑屏障，且被预测具有良好的安全性。针对棒状菌素A与游离酶及结合酶的分子动力学模拟结果显示，两类复合物在整个模拟周期内均保持稳定。鉴于内生菌来源的棒状菌素A对四种选定靶点的优异抑制活性、血脑屏障穿透能力、良好的成药性以及与酶结合后的复合物稳定性，其是开发新型神经治疗药物的优质候选化合物，可开展进一步研究。本文由Ramaswamy H. Sarma通讯。