Department of Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine, Faculty of Pharmacy, University of Valencia, Burjassot, Valencia 46100, Spain.
Molecular Topology and Drug Design Unit. Department of Physical Chemistry, University of Valencia, Burjassot, Valencia 46100, Spain.
J Agric Food Chem. 2024 Feb 7;72(5):2482-2491. doi: 10.1021/acs.jafc.3c05258. Epub 2024 Jan 24.
In a previously published study, the authors devised a molecular topology QSAR (quantitative structure-activity relationship) approach to detect novel fungicides acting as inhibitors of chitin deacetylase (CDA). Several of the chosen compounds exhibited noteworthy activity. Due to the close relationship between chitin-related proteins present in fungi and other chitin-containing plant-parasitic species, the authors decided to test these molecules against nematodes, based on their negative impact on agriculture. From an overall of 20 fungal CDA inhibitors, six showed to be active against . These experimental results made it possible to develop two new molecular topology-based QSAR algorithms for the rational design of potential nematicides with CDA inhibitor activity for crop protection. Linear discriminant analysis was employed to create the two algorithms, one for identifying the chemo-mathematical pattern of commercial nematicides and the other for identifying nematicides with activity on CDA. After creating and validating the QSAR models, the authors screened several natural and synthetic compound databases, searching for alternatives to current nematicides. Finally one compound, the N2-(dimethylsulfamoyl)--{2-[(2-methyl-2-propanyl)sulfanyl]ethyl}-N2-phenylglycinamide or nematode chitin deacetylase inhibitor, was selected as the best candidate and was further investigated both in silico, through molecular docking and molecular dynamic simulations, and in vitro, through specific experimental assays. The molecule shows favorable binding behavior on the catalytic pocket of CDA and the experimental assays confirm potential nematicide activity.
在之前发表的一项研究中，作者设计了一种分子拓扑定量构效关系（QSAR）方法，用于检测作为几丁质脱乙酰酶（CDA）抑制剂的新型杀菌剂。选择的几种化合物表现出了显著的活性。由于真菌中存在的几丁质相关蛋白与其他含几丁质的植物寄生物种之间存在密切关系，作者决定根据这些分子对农业的负面影响，对这些分子进行线虫测试。在总共 20 种真菌 CDA 抑制剂中，有 6 种对 表现出活性。这些实验结果使得有可能开发两种基于新分子拓扑的 QSAR 算法，用于合理设计具有 CDA 抑制剂活性的潜在杀线虫剂，以保护作物。线性判别分析用于创建这两种算法，一种用于识别商品化杀线虫剂的化学数学模式，另一种用于识别具有 CDA 活性的杀线虫剂。在创建和验证 QSAR 模型后，作者筛选了几个天然和合成化合物数据库，寻找替代当前杀线虫剂的替代品。最后，一种化合物，N2-（二甲氨基磺酰基）-{2-[(2-甲基-2-丙基)硫基]乙基}-N2-苯基甘氨酸酰胺或线虫几丁质脱乙酰酶抑制剂，被选为最佳候选物，并进一步通过分子对接和分子动力学模拟进行了计算机模拟研究，以及通过特定的实验检测进行了体外研究。该分子在 CDA 的催化口袋中表现出良好的结合行为，实验检测证实了潜在的杀线虫活性。
