基于配体和结构发现含磷化合物作为潜在的金属蛋白酶抑制剂。

IF 2.3 3区 环境科学与生态学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Y Cañizares-Carmenate, Y Perera-Sardiña, Y Marrero-Ponce, R Díaz-Amador, F Torrens, J A Castillo-Garit
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引用次数: 0

摘要

本研究提出了一种结合配体和基于结构的虚拟筛选工具的方法,用于鉴定作为锌金属蛋白酶抑制剂的含磷化合物。首先,我们利用龙分子描述符建立了一个线性判别分析分类模型,该模型已根据经合组织(OECD)原则进行了广泛验证。该模型简单、稳健、稳定,具有良好的判别能力。此外,该模型还具有明确的适用范围,可用于药物库数据库的虚拟筛选。其次,对确定的化合物进行了对接实验,这些化合物与热溶解酶的结合能良好。考虑到含磷化合物的潜在毒性,根据 Protox II 对其毒理学特征进行了评估。在评估的 5 个分子中,有 2 个在 LD50 较小的情况下显示出致癌和致突变的潜力,不建议用作药物,而有 3 个被归类为无毒,可作为开发新的血管活性金属蛋白酶抑制剂药物的起点。根据分子动力学模拟,其中两种药物显示出与活性位点稳定的相互作用,并保持与金属的配位。QSAR、对接和分子动力学结果之间的一致性很高,显示了这些工具结合使用的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ligand and structure-based discovery of phosphorus-containing compounds as potential metalloproteinase inhibitors.

In this study, a methodology is proposed, combining ligand- and structure-based virtual screening tools, for the identification of phosphorus-containing compounds as inhibitors of zinc metalloproteases. First, we use Dragon molecular descriptors to develop a Linear Discriminant Analysis classification model, which is widely validated according to the OECD principles. This model is simple, robust, stable and has good discriminating power. Furthermore, it has a defined applicability domain and it is used for virtual screening of the DrugBank database. Second, docking experiments are carried out on the identified compounds that showed good binding energies to the enzyme thermolysin. Considering the potential toxicity of phosphorus-containing compounds, their toxicological profile is evaluated according to Protox II. Of the five molecules evaluated, two show carcinogenic and mutagenic potential at small LD50, not recommended as drugs, while three of them are classified as non-toxic, and could constitute a starting point for the development of new vasoactive metalloprotease inhibitor drugs. According to molecular dynamics simulation, two of them show stable interactions with the active site maintaining coordination with the metal. A high agreement is evident between QSAR, docking and molecular dynamics results, demonstrating the potentialities of the combination of these tools.

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来源期刊
CiteScore
5.20
自引率
20.00%
发文量
78
审稿时长
>24 weeks
期刊介绍: SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.
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