基于结构的新型苯甲酸衍生物作为克氏锥虫 trans-sialidase 抑制剂的虚拟筛选。
Structure-Based Virtual Screening of New Benzoic Acid Derivatives as Trypanosoma cruzi Trans-sialidase Inhibitors.
机构信息
Laboratorio de Biotecnologia Farmaceutica, Centro de Biotecnologia Genomica, Instituto Politecnico Nacional, 88710, Reynosa, Mexico.
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Quimica Organica, Buenos Aires, Argentina.
出版信息
Med Chem. 2021;17(7):724-731. doi: 10.2174/1573406416666200506084611.
BACKGROUND
Chagas disease, caused by the parasite Trypanosoma cruzi, represents a worldwide epidemiological, economic, and social problem. In the last decades, the trans-sialidase enzyme of Trypanosoma cruzi has been considered an attractive target for the development of new agents with potential trypanocidal activity.
OBJECTIVE
In this work, the aim was to find new potential non-sugar trans-sialidase inhibitors using benzoic acid as a scaffold.
METHODS
A structure-based virtual screening of the ZINC15 database was carried out. Additionally, the enzyme and trypanocidal activity of the selected compounds was determined.
RESULTS
The results of this work detected 487 compounds derived from benzoic acid as potential transsialidase inhibitors with a more promising binding energy value (< -7.7 kcal/mol) than the known inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA). In particular, two lead compounds, V1 and V2, turned out to be promising trans-sialidase inhibitors. Even though the trypanocidal activity displayed was low, these compounds showed trans-sialidase inhibition values of 87.6% and 29.6%, respectively.
CONCLUSION
Structure-based virtual screening using a molecular docking approach is a useful method for the identification of new trans-sialidase inhibitors.
背景
由寄生虫克氏锥虫引起的恰加斯病是一个全球性的流行病学、经济和社会问题。在过去几十年中，克氏锥虫的 trans-sialidase 酶已被认为是开发具有潜在杀锥虫活性的新药物的有吸引力的靶标。
目的
本工作旨在以苯甲酸为骨架寻找新的潜在非糖基 trans-sialidase 抑制剂。
方法
对 ZINC15 数据库进行基于结构的虚拟筛选。此外，还测定了所选化合物的酶和杀锥虫活性。
结果
这项工作的结果检测到 487 种源自苯甲酸的化合物，它们可能是 transsialidase 抑制剂，其结合能值（< -7.7 kcal/mol）比已知的抑制剂 2,3-去氢-2-脱氧-N-乙酰神经氨酸（DANA）更有前途。特别是两种先导化合物 V1 和 V2 被证明是有前途的 trans-sialidase 抑制剂。尽管显示的杀锥虫活性较低，但这些化合物的 trans-sialidase 抑制率分别为 87.6%和 29.6%。
结论
使用分子对接方法进行基于结构的虚拟筛选是识别新的 trans-sialidase 抑制剂的一种有用方法。
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