Exploring Low-Toxicity Chemical Space with Deep Learning for Molecular Generation

Creating a wide range of new compounds that not only have ideal pharmacological properties but also easily pass long-term toxicity evaluation is still a challenging task in current drug discovery. In this study, we developed a conditional generative model by combining a semisupervised variational autoencoder (SSVAE) with an MGA toxicity predictor. Our aim is to generate molecules with low toxicity, good drug-like properties, and structural diversity. For multiobjective optimization, we have developed a method with hierarchical constraints on the toxicity space of small molecules to generate drug-like small molecules, which can also minimize the effect on the diversity of generated results. The evaluation results of the metrics indicate that the developed model has good effectiveness, novelty, and diversity. The generated molecules by this model are mainly distributed in low-toxicity regions, which suggests that our model can efficiently constrain the generation of toxic structures. In contrast to simply filtering toxic ones after generation, the low-toxicity molecular generative model can generate molecules with structural diversity. Our strategy can be used in target-based drug discovery to improve the quality of generated molecules with low-toxicity, drug-like, and highly active properties.