运用计算机方法揭示抗利什曼病先导化合物的作用靶点。
Unveiling the Targets Involved in the Quest of Antileishmanial Leads Using In silico Methods.
机构信息
Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
出版信息
Curr Drug Targets. 2020;21(7):681-712. doi: 10.2174/1389450121666200128112948.
BACKGROUND
Leishmaniasis is a neglected tropical disease associated with several clinical manifestations, including cutaneous, mucocutaneous, and visceral forms. As currently available drugs have some limitations (toxicity, resistance, among others), the target-based identification has been an important approach to develop new leads against leishmaniasis. The present study aims to identify targets involved in the pharmacological action of potent antileishmanial compounds.
METHODS
The literature information regarding molecular interactions of antileishmanial compounds studied over the past half-decade is discussed. The information was obtained from databases such as Wiley, SciFinder, Science Direct, National Library of Medicine, American Chemical Society, Scientific Electronic Library Online, Scopus, Springer, Google Scholar, Web of Science, etc. Results: Numerous in vitro antileishmanial compounds showed affinity and selective interactions with enzymes such as arginase, pteridine reductase 1, trypanothione reductase, pyruvate kinase, among others, which are crucial for the survival and virulence of the Leishmania parasite.
CONCLUSION
The in-silico activity of small molecules (enzymes, proteins, among others) might be used as pharmacological tools to develop candidate compounds for the treatment of leishmaniasis. As some pharmacologically active compounds may act on more than one target, additional studies of the mechanism (s) of action of potent antileishmanial compounds might help to better understand their pharmacological action. Also, the optimization of promising antileishmanial compounds might improve their biological activity.
背景
利什曼病是一种被忽视的热带病,与多种临床表现有关,包括皮肤、黏膜和内脏形式。由于目前可用的药物存在一些局限性(毒性、耐药性等),基于靶点的鉴定已成为开发抗利什曼病新先导化合物的重要方法。本研究旨在鉴定参与有效抗利什曼化合物药理作用的靶点。
方法
讨论了过去半个世纪中研究的抗利什曼化合物的分子相互作用的文献信息。这些信息是从 Wiley、SciFinder、Science Direct、美国国立医学图书馆、美国化学学会、Scientific Electronic Library Online、Scopus、Springer、Google Scholar、Web of Science 等数据库中获得的。
结果
许多体外抗利什曼化合物与酶(如精氨酸酶、蝶呤还原酶 1、谷胱甘肽还原酶、丙酮酸激酶等)表现出亲和力和选择性相互作用,这些酶对利什曼寄生虫的生存和毒力至关重要。
结论
小分子(酶、蛋白质等)的计算机活性可作为药理学工具,用于开发治疗利什曼病的候选化合物。由于一些具有药理活性的化合物可能作用于不止一个靶点,因此对有效抗利什曼化合物的作用机制的进一步研究可能有助于更好地理解其药理作用。此外,优化有前途的抗利什曼化合物可能会提高其生物活性。