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首页> 外文期刊>Network Modeling Analysis in Health Informatics and Bioinformatics >Computational screening and ADMET-based study for targeting Plasmodium S-adenosyl-L-homocysteine hydrolase: top scoring inhibitors
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Computational screening and ADMET-based study for targeting Plasmodium S-adenosyl-L-homocysteine hydrolase: top scoring inhibitors

机译：靶向疟原虫S-腺苷-1-同型半胱氨酸酶水解酶的计算筛选和备用研究：顶层评分抑制剂

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摘要

S-adenosyl-L-homocysteine hydrolase (SAHH) is a ubiquitous enzyme that plays a significant role in methylation-based processes by maintaining the intracellular balance between S-adenosylhomocysteine and S-adenosylmethionine. In the past years, some analogs and derivatives of aristeromycin have been reported as a potential inhibitor of Plasmodium falciparum's SAHH (PfSAHH), but no effective therapy has been developed yet. In our previous studies, molecular dynamics simulation study of 2-fluoroaristeromycin in complex with PfSAHH was carried out, and a stable complex with favorable binding energy and interaction was observed. In the presented work, 2-fluoroaristeromycin was used as a central compound for finding the vast set of similar compounds using PubChem database search (65 compounds), pharmacophore-based search (1219 compounds) and ZINC database search for biogenic compounds (approximately 1, 82000 compounds). All these compounds were docked with PfSAHH drug target to screen compounds with energetically favorable binding and stable conformation. Binding energy and different ADMET based parameters were used for screening some potential compound from each set. Binding affinity and interaction of top scoring 15 compounds from the biogenic subset were again evaluated using other docking tools such as AutoDock and AutoDock Vina. These top scoring compounds satisfy the binding and most of the ADMET parameters, and their activity can be further optimized to find a more potent inhibitor of PfSAHH.
机译：S-腺苷-1-同型半胱氨酸水解酶（SAHH）是一种普遍存在的酶，其通过维持S-腺苷在S-腺细胞和S-腺苷甲基硫氨酸之间的细胞内平衡，在基于甲基化的过程中起着显着作用。在过去几年中，一些类似物霉素的类似物和衍生物被报告为疟原虫肉体萨赫赫（PFSAHH）的潜在抑制剂，但尚无有效的治疗。在先前的研究中，进行了与PFSAHH复合物中的2-氟过霉素的分子动力学模拟研究，并观察到具有良好的结合能量和相互作用的稳定复合物。在所呈现的作品中，使用2-氟过程序霉素用作使用Pubchem数据库搜索（65种化合物），基于Pharmacophore的搜索（1219化合物）和锌数据库搜索生物化合物（约1， 82000化合物）。将所有这些化合物与PFSAHH药物靶靶向停靠，以筛选化合物，具有能量有利的结合和稳定的构象。使用绑定能量和基于备用的参数用于筛选每个组的一些潜在化合物。使用其他对接工具（如Autodock和Autodock Vina），再次评估来自生物群的底部得分15化合物的结合亲和力和相互作用。这些顶部得分化合物满足了结合和大部分备用参数，并且可以进一步优化它们的活性以找到更有效的PFSAHH抑制剂。

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