Discovery of novel flavivirus inhibitors

项目4--摘要 该项目的目标是发现新的黄病毒抑制剂。诺华公司拥有登革热15年的历史数据 聚合酶、蛋白酶和核苷/核苷酸收集。这些数据集是机器学习的理想选择 PQSAR针对这些已证实的抗病毒靶点，合理地探索/设计新的化学物质。我们将继续追查 三个目标。(I)发现一种NS5核苷聚合酶抑制剂。核苷/核苷酸抑制剂是主要的 临床批准的抗病毒药物类别。它具有阻挡能力强、光谱范围广等优点。 抗病毒活性。后一种优势可以通过测试 核苷/核苷酸化合物抗不同家族的病毒。(Ii)发现NS5非核苷 聚合酶抑制剂。我们已经从以前的HTS生成了一个登革热聚合酶抑制剂的大型数据集 竞选活动。这些HTS活动是使用不同的生化和生物物理分析方法进行的。一个 专有的机器学习平台，加上现有的生化和结构生物学工具，将 被用来指导理性的药物发现。(3)发现一种NS3蛋白水解酶抑制剂。我们将开发一种非 利用我们先前在登革热蛋白水解酶方面的专业知识(例如， 登革热NS2B辅因子和蛋白酶与抑制剂的复合体的共晶体结构)和诺华的其他 蛋白酶项目。

PROJECT 4 – ABSTRACT The goal of this project is to discover novel flavivirus inhibitors. Novartis has 15-year historical data in dengue polymerase, protease, and nucleoside/nucleotide collection. The data sets are ideal for machine-learning pQSAR to rationally explore/design new chemical matters against these proven antiviral targets. We will pursue three aims. (i) Discover a NS5 nucleoside polymerase inhibitor. Nucleoside/nucleotide inhibitors form the major class of clinically approved antiviral drugs. It has the advantages of high resistance barrier and broad-spectrum antiviral activity. The latter advantage can be capitalized to synergize with other projects by testing the nucleoside/nucleotide compounds against viruses from different families. (ii) Discover a NS5 non-nucleoside polymerase inhibitor. We have generated a large dataset of dengue polymerase inhibitors from previous HTS campaigns. These HTS campaigns were performed using different biochemical and biophysical assays. A proprietary machine-learning platform, together with established biochemical and structural biological tools, will be used to guide a rational drug discovery. (iii) Discover a NS3 protease inhibitor. We will develop a non- peptidomimetic inhibitor of flavivirus protease, leveraging on our previous expertise on dengue protease (e.g., cocrystal structure of dengue NS2B cofactor and protease in complex with an inhibitor) and Novartis’ other protease projects.