Lima Marilia N N, Melo-Filho Cleber C, Cassiano Gustavo C, Neves Bruno J, Alves Vinicius M, Braga Rodolpho C, Cravo Pedro V L, Muratov Eugene N, Calit Juliana, Bargieri Daniel Y, Costa Fabio T M, Andrade Carolina H
LabMol - Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goiás, Goiânia, Brazil.
Laboratory of Tropical Diseases - Prof. Dr. Luiz Jacintho da Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, UNICAMP, Campinas, Brazil.
Front Pharmacol. 2018 Mar 6;9:146. doi: 10.3389/fphar.2018.00146. eCollection 2018.
Malaria is a life-threatening infectious disease caused by parasites of the genus , affecting more than 200 million people worldwide every year and leading to about a half million deaths. Malaria parasites of humans have evolved resistance to all current antimalarial drugs, urging for the discovery of new effective compounds. Given that the inhibition of deoxyuridine triphosphatase of (dUTPase) induces wrong insertions in plasmodial DNA and consequently leading the parasite to death, this enzyme is considered an attractive antimalarial drug target. Using a combi-QSAR (quantitative structure-activity relationship) approach followed by virtual screening and experimental evaluation, we report herein the discovery of novel chemical scaffolds with potency against asexual blood stages of both multidrug-resistant and sensitive strains and against sporogonic development of . We developed 2D- and 3D-QSAR models using a series of nucleosides reported in the literature as dUTPase inhibitors. The best models were combined in a consensus approach and used for virtual screening of the ChemBridge database, leading to the identification of five new virtual dUTPase inhibitors. Further testing on multidrug-resistant (W2) and sensitive (3D7) parasites showed that compounds LabMol-144 and LabMol-146 demonstrated fair activity against both strains and presented good selectivity versus mammalian cells. In addition, LabMol-144 showed good inhibition of ookinete formation, demonstrating that hit-to-lead optimization based on this compound may also lead to new antimalarials with transmission blocking activity.
疟疾是一种由疟原虫属寄生虫引起的危及生命的传染病，每年影响全球超过2亿人，并导致约50万人死亡。人类疟原虫已对所有目前的抗疟药物产生耐药性，因此迫切需要发现新的有效化合物。鉴于抑制疟原虫脱氧尿苷三磷酸酶（dUTPase）会在疟原虫DNA中诱导错误插入，从而导致寄生虫死亡，这种酶被认为是一个有吸引力的抗疟药物靶点。通过结合定量构效关系（combi-QSAR）方法，随后进行虚拟筛选和实验评估，我们在此报告发现了新型化学骨架，它们对多药耐药和敏感菌株的无性血液阶段以及疟原虫的孢子生殖发育均具有效力。我们使用文献中报道的一系列作为dUTPase抑制剂的核苷开发了二维和三维定量构效关系模型。最佳模型以一种共识方法进行组合，并用于对ChemBridge数据库进行虚拟筛选，从而鉴定出五种新的虚拟dUTPase抑制剂。对多药耐药（W2）和敏感（3D7）寄生虫的进一步测试表明，化合物LabMol-144和LabMol-146对两种菌株均表现出良好活性，并且对哺乳动物细胞具有良好的选择性。此外，LabMol-144对动合子形成表现出良好的抑制作用，这表明基于该化合物的从苗头化合物到先导化合物的优化也可能产生具有传播阻断活性的新型抗疟药物。
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