DASH: Dynamic Attention-Based Substructure Hierarchy for Partial Charge Assignment

We present a robust and computationally efficient approach for assigning partial charges of atoms in molecules. The method is based on a hierarchical tree constructed from attention values extracted from a graph neural network (GNN), which was trained to predict atomic partial charges from accurate quantum-mechanical (QM) calculations. The resulting dynamic attention-based substructure hierarchy (DASH) approach provides fast assignment of partial charges with the same accuracy as the GNN itself, is software-independent, and can easily be integrated in existing parametrization pipelines as shown for the Open force field (OpenFF). The implementation of the DASH workflow, the final DASH tree, and the training set are available as open source / open data from public repositories

Deep interactome learning for de novo drug design

De novo drug design aims to generate molecules from scratch that possess specific chemical and pharmacological properties. We present a computational approach utilizing interactome-based deep learning for ligand- and structure-based generation of drug-like molecules. This method capitalizes on the unique strengths of both graph neural networks and chemical language models, offering an alternative to the need for application-specific reinforcement, transfer, or few-shot learning. It allows for the construction of compound libraries tailored to possess specific bioactivity, synthesizability, and structural novelty. In order to proactively evaluate the deep interactome learning framework for structure-based drug design, potential new ligands targeting the binding site of the human peroxisome proliferator-activated receptor (PPAR) subtype gamma were generated. The top-ranking designs were chemically synthesized and biophysically and biochemically characterized. Potent PPAR partial agonists were identified, demonstrating favorable activity and the desired selectivity profiles for both nuclear receptors and off-target interactions. Crystal structure determination of the ligand-receptor complex confirmed the anticipated binding mode. This successful outcome positively advocates interactome-based de novo design for application in bioorganic and medicinal chemistry, enabling the creation of innovative bioactive molecules