Scaffold-Retained Structure Generator to Exhaustively Create Molecules in an Arbitrary Chemical Space

The construction of a virtual library (VL) consisting of novel molecules based on structure-activity relationships is crucial for lead optimization in rational drug design. In this study, we propose a novel scaffold-retained structure generator, EMPIRE (Exhaustive Molecular library Production In a scaffold-REtained manner), to create novel molecules in an arbitrary chemical space. By combining a deep learning model-based generator and a building block-based generator, the proposed method efficiently provides a VL consisting of molecules that retain the input scaffold and contain unique arbitrary substructures. The proposed method enables us to construct rational VLs located in unexplored chemical spaces containing molecules with unique skeletons (e.g., bicyclo[1.1.1]pentane and cubane) or elements (e.g., boron and silicon). We expect EMPIRE to contribute to efficient drug design with unique substructures by virtual screening.