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。诺华有15年的登革热历史数据 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，以合理地探索/设计新的化学物质对这些已证实的抗病毒靶点。我们将奉行 三个目标。(i)发现NS 5核苷聚合酶抑制剂。核苷/核苷酸抑制剂形成主要的 临床批准的一类抗病毒药物。它具有高阻障、广谱等优点 抗病毒活性。后一个优势可以通过测试 核苷/核苷酸化合物对抗来自不同科的病毒。(ii)发现NS 5非核苷 聚合酶抑制剂我们已经从以前的HTS中生成了一个大型登革热聚合酶抑制剂数据集 竞选使用不同的生物化学和生物物理测定进行这些HTS活动。一 专有的机器学习平台，以及已建立的生物化学和结构生物学工具，将 用于指导合理的药物发现。(iii)发现NS 3蛋白酶抑制剂。我们将开发一个非- 黄病毒蛋白酶的拟肽抑制剂，利用我们以前对登革热蛋白酶的专业知识（例如， 登革NS 2B辅因子和蛋白酶与抑制剂复合的共晶体结构）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.