De Novo Molecule Design Using Molecular Generative Models Constrained by Ligand-Protein Interactions

In recent years, molecular deep generative models have attracted much attention for its application in de novo drug design. The data-driven molecular deep generative model approximates the high dimensional distribution of the chemical space through learning from a large number of molecular structural data. So far, most of the molecular generative models rely on purely 2D ligand information in structure generation. Here, we propose a novel molecular deep generative model which adopts a recurrent neural network architecture coupled with a ligand-protein interaction fingerprint as constraints. The fingerprint was constructed on ligand docking poses and represents the 3D binding mode of ligands in the protein pocket. In the current work, generative models constrained with interaction fingerprints were trained and compared with normal RNN models. It has been shown that models trained with constraints of ligand-protein interaction fingerprint have a clear tendency to generating compounds maintaining similar binding modes. Our results demonstrate the potential application of the interaction fingerprint-constrained generative model for the targeted molecule generation and guided exploration on the drug-like chemical space.