Navigating Chemical Space By Interfacing Generative Artificial Intelligence and Molecular Docking

Here we report the testing and application of a simple, structure-aware framework to design target-specific screening libraries for drug development. Our approach combines advances in generative artificial intelligence (AI) with conventional molecular docking to rapidly explore chemical space conditioned on the unique physiochemical properties of the active site of a biomolecular target. As a proof-of-concept, we used our framework to construct a focused library for cyclin-dependent kinase type-2 (CDK2). We then used it to rapidly generate a library specific to the active site of the main protease (M pro ) of the SARS-CoV-2 virus, which causes COVID-19. By comparing approved and experimental drugs to compounds in our library, we also identified six drugs, namely, Naratriptan, Etryptamine, Panobinostat, Procainamide, Sertraline, and Lidamidine, as possible SARS-CoV-2 M pro targeting compounds and, as such, potential drug repurposing candidates. To complement the open-science COVID-19 drug discovery initiatives, we make our SARS-CoV-2 M pro library fully accessible to the research community ( https://github.com/atfrank/SARS-CoV-2 ).