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.