De Novo Molecule Design Through the Molecular Generative Model Conditioned by 3D Information of Protein Binding Sites

De novo molecule design through the molecular generative model has gained increasing attention in recent years. Here, a novel generative model was proposed by integrating the three-dimensional (3D) structural information of the protein binding pocket into the conditional RNN (cRNN) model to control the generation of drug-like molecules. In this model, the composition of the protein binding pocket is effectively characterized through a coarse-grain strategy and the 3D information of the pocket can be represented by the sorted eigenvalues of the Coulomb matrix (EGCM) of the coarse-grained atoms composing the binding pocket. In current work, we used our EGCM method and a previously reported binding pocket descriptor, DeeplyTough, to train cRNN models and evaluated their performance. It has been shown that the model trained with the constraint of protein environment information has a clear tendency on generating compounds with higher similarity to the original X-ray-bound ligand than the normal RNN model and also better docking scores. Our results demonstrate the potential application of the controlled generative model for the targeted molecule generation and guided exploration on the drug-like chemical space.