Ramos Paulo Ricardo Pimenta da Silva, Mottin Melina, Lima Caroline Sprengel, Assis Letícia R, de Oliveira Ketllyn Zagato, Mesquita Nathalya Cristina de Moraes Roso, Cassani Natasha Marques, Santos Igor Andrade, Borba Joyce Villa Verde Bastos, Fiaia Costa Vinícius Alexandre, Neves Bruno Junior, Guido Rafael Victorio Carvalho, Oliva Glaucius, Jardim Ana Carolina Gomes, Regasini Luis Octávio, Andrade Carolina Horta
LabMol-Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmácia, Universidade Federal de Goiás, Goiania 74605-170, Brazil.
Laboratory of Antibiotics and Chemotherapeutics (LAC), Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (Unesp), Sao José do Rio Preto 15054-000, Brazil.
Pharmaceuticals (Basel). 2022 Nov 30;15(12):1493. doi: 10.3390/ph15121493.
Although the past epidemic of Zika virus (ZIKV) resulted in severe neurological consequences for infected infants and adults, there are still no approved drugs to treat ZIKV infection. In this study, we applied computational approaches to screen an in-house database of 77 natural and semi-synthetic compounds against ZIKV NS5 RNA-dependent RNA-polymerase (NS5 RdRp), an essential protein for viral RNA elongation during the replication process. For this purpose, we integrated computational approaches such as binding-site conservation, chemical space analysis and molecular docking. As a result, we prioritized nine virtual hits for experimental evaluation. Enzymatic assays confirmed that pedalitin and quercetin inhibited ZIKV NS5 RdRp with IC values of 4.1 and 0.5 µM, respectively. Moreover, pedalitin also displayed antiviral activity on ZIKV infection with an EC of 19.28 µM cell-based assays, with low toxicity in Vero cells (CC = 83.66 µM) and selectivity index of 4.34. These results demonstrate the potential of the natural compounds pedalitin and quercetin as candidates for structural optimization studies towards the discovery of new anti-ZIKV drug candidates.
尽管过去寨卡病毒（ZIKV）疫情给受感染的婴儿和成人带来了严重的神经后果，但目前仍没有获批用于治疗ZIKV感染的药物。在本研究中，我们应用计算方法，针对一个包含77种天然和半合成化合物的内部数据库，筛选抗ZIKV NS5 RNA依赖性RNA聚合酶（NS5 RdRp）的化合物，NS5 RdRp是病毒复制过程中病毒RNA延伸所必需的蛋白质。为此，我们整合了结合位点保守性、化学空间分析和分子对接等计算方法。结果，我们筛选出9个虚拟命中化合物用于实验评估。酶活性测定证实，pedalitin和槲皮素对ZIKV NS5 RdRp具有抑制作用，其IC值分别为4.1和0.5 μM。此外，在基于细胞的试验中，pedalitin对ZIKV感染也表现出抗病毒活性，其EC为19.28 μM，在Vero细胞中的毒性较低（CC = 83.66 μM），选择性指数为4.34。这些结果表明，天然化合物pedalitin和槲皮素具有作为结构优化研究候选物的潜力，以发现新的抗ZIKV药物候选物。
