Laboratory for Computational Physiology, Department of Biology, Faculty of Science, Razi University, Kermanshah, 67149-67346, Iran.
BMC Complement Med Ther. 2023 Nov 21;23(1):421. doi: 10.1186/s12906-023-04241-z.
Myrtus communis L. (MC) has been used in Mesopotamian medicine. Here, the cholinesterase (ChE) inhibitory potential of its methyl alcohol extracts has been investigated and computationally dissected.
The ChE inhibition has been measured based on usual Ellman's colorimetric method compared to a canonical ChE inhibitor, eserine. Through a deep text mining, the structures of phytocompounds (= ligands) of MC were curated from ChemSpider, PubChem, and ZINC databases and docked into protein targets, AChE (PDB 1EVE) and BChE (PDB 1P0I) after initial in silico preparedness and binding affinity (BA; kcal/mol) reported as an endpoint. The calculation of ADMET (absorption, distribution, metabolism, excretion, and toxicity) features of phytocompounds were retrieved from SwissADME ( http://www.swissadme.ch/ ) and admetSAR software to predict the drug-likeness or lead-likeness fitness. The Toxtree v2.5.1, software platforms ( http://toxtree.sourceforge.net/ ) have been used to predict the class of toxicity of phytocompounds. The STITCH platform ( http://stitch.embl.de ) has been employed to predict ChE-chemicals interactions.
The possible inhibitory activities of AChE of extracts of leaves and berries were 37.33 and 70.00%, respectively as compared to that of eserine while inhibitory BChE activities of extracts of leaves and berries of MC were 19.00 and 50.67%, respectively as compared to that of eserine. Phytochemicals of MC had BA towards AChE ranging from -7.1 (carvacrol) to -9.9 (ellagic acid) kcal/mol. In this regard, alpha-bulnesene, (Z)-gamma-Bisabolene, and beta-bourbonene were top-listed low toxic binders of AChE, and (Z)-gamma-bisabolene was a more specific AChE binder. Alpha-cadinol, estragole, humulene epoxide II, (a)esculin, ellagic acid, patuletin, juniper camphor, linalyl anthranilate, and spathulenol were high class (Class III) toxic substances which among others, patuletin and alpha-cadinol were more specific AChE binders. Among intermediate class (Class II) toxic substances, beta-chamigrene was a more specific AChE binder while semimyrtucommulone and myrtucommulone A were more specific BChE binders.
In sum, the AChE binders derived from MC were categorized mostly as antiinsectants (e.g., patuletin and alpha-cardinal) due to their predicted toxic classes. It seems that structural amendment and stereoselective synthesis like adding sulphonate or sulphamate groups to these phytocompounds may make them more suitable candidates for considering in preclinical investigations of Alzheimer's disease.
桃金娘（MC）已在美索不达米亚医学中使用。在这里，研究了其甲醇提取物的胆碱酯酶（ChE）抑制潜力，并通过计算方法进行了剖析。
通过深度文本挖掘，从 ChemSpider、PubChem 和 ZINC 数据库中整理了 MC 的植物化合物（=配体）的结构，并将其对接入蛋白靶标 AChE（PDB 1EVE）和 BChE（PDB 1P0I）中，根据通常的 Ellman 比色法进行了初始准备，报告了结合亲和力（BA；kcal/mol）作为终点。通过 SwissADME（http://www.swissadme.ch/）和 admetSAR 软件从植物化合物中检索吸收，分布，代谢，排泄和毒性（ADMET）特征的计算，并预测药物样或铅样适应性。Toxtree v2.5.1，软件平台（http://toxtree.sourceforge.net/）用于预测植物化合物的毒性类别。使用 STITCH 平台（http://stitch.embl.de）预测 ChE-化学物质相互作用。
与 eserine 相比，叶和浆果提取物对 AChE 的可能抑制活性分别为 37.33%和 70.00%，而叶和浆果 MC 提取物对 BChE 的抑制活性分别为 19.00%和 50.67%。MC 的植物化学物质对 AChE 的 BA 范围为-7.1（香芹酚）至-9.9（鞣花酸）kcal/mol。在这方面，α-侧柏烯，（Z）-γ-双环大根香叶烯和β-波旁烯是 AChE 的顶级低毒结合物，（Z）-γ-双环大根香叶烯是更具特异性的 AChE 结合物。α-贝壳杉醇，黄樟醚，葎草环氧二烯，（a）表没食子儿茶素没食子酸酯，鞣花酸，帕图林，杜松樟脑，丁香醛，香叶基邻氨基苯甲酸和蛇麻烯醇是高毒性（III 类）物质，其中帕图林和α-贝壳杉醇是更具特异性的 AChE 结合物。在中间类（II 类）有毒物质中，β-卡波烯是更具特异性的 AChE 结合物，而半甜橙酮和甜橙酮 A 是更具特异性的 BChE 结合物。
总的来说，源自 MC 的 AChE 结合物由于其预测的毒性类别而大多被归类为杀虫剂（例如，帕图林和α-卡德林）。似乎通过添加磺酸盐或磺酰胺基团等结构修饰和立体选择性合成，这些植物化合物可能更适合考虑在阿尔茨海默病的临床前研究中。
