Approach for the Design of Covalent Protein Kinase Inhibitors via Focused Deep Generative Modeling.

Deep machine learning is expanding the conceptual framework and capacity of computational compound design, enabling new applications through generative modeling. We have explored the systematic design of covalent protein kinase inhibitors by learning from kinome-relevant chemical space, followed by focusing on an exemplary kinase of interest. Covalent inhibitors experience a renaissance in drug discovery, especially for targeting protein kinases. However, computational design of this class of inhibitors has thus far only been little investigated. To this end, we have devised a computational approach combining fragment-based design and deep generative modeling augmented by three-dimensional pharmacophore screening. This approach is thought to be particularly relevant for medicinal chemistry applications because it combines knowledge-based elements with deep learning and is chemically intuitive. As an exemplary application, we report for Bruton's tyrosine kinase (BTK), a major drug target for the treatment of inflammatory diseases and leukemia, the generation of novel candidate inhibitors with a specific chemically reactive group for covalent modification, requiring only little target-specific compound information to guide the design efforts. Newly generated compounds include known inhibitors and characteristic substructures and many novel candidates, thus lending credence to the computational approach, which is readily applicable to other targets.