Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil.
Laboratório de Bioquímica de Tripanossomatídeos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil.
Molecules. 2021 Jun 10;26(12):3537. doi: 10.3390/molecules26123537.
Epoxy-α-lapachone (Lap) and Epoxymethyl-lawsone (Law) are oxiranes derived from Lapachol and have been shown to be promising drugs for Leishmaniases treatment. Although, it is known the action spectrum of both compounds affect the spp. multiplication, there are gaps in the molecular binding details of target enzymes related to the parasite's physiology. Molecular docking assays simulations were performed using DockThor server to predict the preferred orientation of both compounds to form stable complexes with key enzymes of metabolic pathway, electron transport chain, and lipids metabolism of spp. This study showed the hit rates of both compounds interacting with lanosterol C-14 demethylase (-8.4 kcal/mol to -7.4 kcal/mol), cytochrome c (-10.2 kcal/mol to -8.8 kcal/mol), and glyceraldehyde-3-phosphate dehydrogenase (-8.5 kcal/mol to -7.5 kcal/mol) according to spp. and assessed compounds. The set of molecular evidence reinforces the potential of both compounds as multi-target drugs for interrupt the network interactions between parasite enzymes, which can lead to a better efficacy of drugs for the treatment of leishmaniases.
环氧-α-拉帕醌（Lap）和环氧甲基拉索醇（Law）是来源于拉帕醇的环氧化物，已被证明是治疗利什曼病的有前途的药物。尽管已知这两种化合物的作用光谱会影响 spp 的繁殖，但与寄生虫生理学相关的靶酶的分子结合细节仍存在空白。使用 DockThor 服务器进行分子对接模拟实验，以预测这两种化合物与代谢途径、电子传递链和 spp 的脂质代谢的关键酶形成稳定复合物的优先取向。这项研究表明，这两种化合物与羊毛甾醇 C-14 脱甲基酶（-8.4 kcal/mol 至-7.4 kcal/mol）、细胞色素 c（-10.2 kcal/mol 至-8.8 kcal/mol）和甘油醛-3-磷酸脱氢酶（-8.5 kcal/mol 至-7.5 kcal/mol）的相互作用的命中率，根据 spp 和评估化合物。这组分子证据增强了这两种化合物作为多靶药物的潜力，以中断寄生虫酶之间的网络相互作用，从而提高治疗利什曼病的药物疗效。
