CogMol: Target-Specific and Selective Drug Design for COVID-19 Using Deep Generative Models

The novel nature of SARS-CoV-2 calls for the development of efficient de novo drug design approaches. In this study, we propose an end-to-end framework, named CogMol (Controlled Generation of Molecules), for designing new drug-like small molecules targeting novel viral proteins with high affinity and off-target selectivity. CogMol combines adaptive pre-training of a molecular SMILES Variational Autoencoder (VAE) and an efficient multi-attribute controlled sampling scheme that uses guidance from attribute predictors trained on latent features. To generate novel and optimal drug-like molecules for unseen viral targets, CogMol leverages a protein-molecule binding affinity predictor that is trained using SMILES VAE embeddings and protein sequence embeddings learned unsupervised from a large corpus. We applied the CogMol framework to three SARS-CoV-2 target proteins: main protease, receptor-binding domain of the spike protein, and non-structural protein 9 replicase.