Deep interactome learning for de novo drug design

19 September 2023, Version 1


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.


Structure-based drug design
Generative Artificial Intelligence
Language models
Graph neural networks

Supplementary materials

Supporting Information: Deep interactome learning for generative drug design
Supporting Information to the main manuscript.


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