Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Prahran, VIC, 3004, Australia; Department of Microbiology and Immunology (Pathology), The University of Melbourne, Parkville, VIC, 3052, Australia.
Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Prahran, VIC, 3004, Australia; School of Science, RMIT University, VIC, 3001, Australia.
Comput Biol Chem. 2020 Jun;86:107234. doi: 10.1016/j.compbiolchem.2020.107234. Epub 2020 Feb 13.
The antidepressant medications that are currently prescribed to patients suffering from major depressive disorder (MDD) have limitations and as a result, there is an urgent need to increase the options that are available. A number of studies have found that natural polyphenols have neuroprotective properties and there is evidence to suggest that they modulate neurotransmitter systems. There are more than 200 phenolic compounds that have been identified in Olea europaea, many of which have not yet been investigated for their potential biological effects. In this study, in silico methods were used to screen the phenolic library from the OliveNet™ database and identify novel lead compounds for proteins implicated in the pathophysiology of MDD. The molecular docking results revealed that the monoamine oxidase enzyme isoforms (MAO-A/MAO-B) had binding specificities for certain phenolic subclasses. The lead ligands that were identified from these subclasses were positioned near the flavin adenine dinucleotide (FAD) cofactor, interacting in a similar manner as known inhibitors. In addition to the MAO enzymes, several phenolic compounds were docked to neurotransmitter transporters and postsynaptic receptors, as well as proteins involved in neuroinflammation, oxidative stress and the endocannabinoid system. Based on the binding affinity, position, orientation and interactions of the lead phenolic compounds identified in this study, it is predicted that they may have antidepressant properties. The results should be validated further using molecular dynamics (MD) simulations, as well as in vivo and in vitro techniques.
目前用于治疗重度抑郁症 (MDD) 患者的抗抑郁药物存在局限性，因此急需增加可用的选择。许多研究发现，天然多酚具有神经保护特性，有证据表明它们可以调节神经递质系统。在油橄榄中已经鉴定出超过 200 种酚类化合物，其中许多尚未研究其潜在的生物学效应。在这项研究中，使用计算方法筛选了 OliveNet™ 数据库中的酚类化合物库，并鉴定了与 MDD 病理生理学相关的蛋白质的新型先导化合物。分子对接结果表明，单胺氧化酶酶同工酶（MAO-A/MAO-B）对某些酚类亚类具有结合特异性。从这些亚类中鉴定出的先导配体位于黄素腺嘌呤二核苷酸 (FAD) 辅因子附近，以与已知抑制剂相似的方式相互作用。除了 MAO 酶外，几种酚类化合物还与神经递质转运体和突触后受体以及参与神经炎症、氧化应激和内源性大麻素系统的蛋白质结合。基于在这项研究中鉴定出的先导酚类化合物的结合亲和力、位置、取向和相互作用，可以预测它们可能具有抗抑郁特性。还应使用分子动力学 (MD) 模拟以及体内和体外技术进一步验证这些结果。
