Laboratory of Antibiotics and Chemotherapeutics (LAQ), Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (Unesp), São José do Rio Preto, SP, Brazil.
Laboratory of Molecular Modeling and Drug Design (LabMol), Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
Bioorg Chem. 2021 Apr;109:104719. doi: 10.1016/j.bioorg.2021.104719. Epub 2021 Feb 11.
Although the widespread epidemic of Zika virus (ZIKV) and its neurological complications are well-known there are still no approved drugs available to treat this arboviral disease or vaccine to prevent the infection. Flavonoids from Pterogyne nitens have already demonstrated anti-flavivirus activity, although their target is unknown. In this study, we virtually screened an in-house database of 150 natural and semi-synthetic compounds against ZIKV NS2B-NS3 protease (NS2B-NS3p) using docking-based virtual screening, as part of the OpenZika project. As a result, we prioritized three flavonoids from P. nitens, quercetin, rutin and pedalitin, for experimental evaluation. We also used machine learning models, built with Assay Central® software, for predicting the activity and toxicity of these flavonoids. Biophysical and enzymatic assays generally agreed with the in silico predictions, confirming that the flavonoids inhibited ZIKV protease. The most promising hit, pedalitin, inhibited ZIKV NS2B-NS3p with an IC of 5 μM. In cell-based assays, pedalitin displayed significant activity at 250 and 500 µM, with slight toxicity in Vero cells. The results presented here demonstrate the potential of pedalitin as a candidate for hit-to-lead (H2L) optimization studies towards the discovery of antiviral drug candidates to treat ZIKV infections.
虽然寨卡病毒（ZIKV）的广泛流行及其神经并发症众所周知，但目前仍没有可用的药物来治疗这种虫媒病毒病，也没有疫苗来预防感染。来自 Pterogyne nitens 的类黄酮已表现出抗黄病毒活性，尽管其靶点未知。在这项研究中，作为 OpenZika 项目的一部分，我们使用基于对接的虚拟筛选技术，对内部 150 种天然和半合成化合物数据库针对 ZIKV NS2B-NS3 蛋白酶（NS2B-NS3p）进行了虚拟筛选。结果，我们优先选择了 P. nitens 的三种类黄酮，槲皮素、芦丁和马蹄素，进行实验评估。我们还使用 Assay Central®软件构建的机器学习模型来预测这些类黄酮的活性和毒性。生物物理和酶测定通常与计算机预测一致，证实这些类黄酮抑制了 ZIKV 蛋白酶。最有前途的候选物马蹄素对 ZIKV NS2B-NS3p 的抑制作用 IC 为 5 μM。在细胞测定中，马蹄素在 250 和 500 μM 时表现出显著的活性，在 Vero 细胞中仅有轻微的毒性。这里呈现的结果表明，马蹄素作为先导化合物优化（H2L）研究的候选物，具有发现抗 ZIKV 感染的抗病毒药物候选物的潜力。
