A pharmacophore-guided deep learning approach for bioactive molecular generation

Abstract

AbstractThe rational design of novel molecules with the desired bioactivity is a critical but challenging task in drug discovery, especially when treating a novel target family or understudied targets. We propose a Pharmacophore-Guided deep learning approach for bioactive Molecule Generation (PGMG). Through the guidance of pharmacophore, PGMG provides a flexible strategy for generating bioactive molecules. PGMG uses a graph neural network to encode spatially distributed chemical features and a transformer decoder to generate molecules. A latent variable is introduced to solve the many-to-many mapping between pharmacophores and molecules to improve the diversity of the generated molecules. Compared to existing methods, PGMG generates molecules with strong docking affinities and high scores of validity, uniqueness, and novelty. In the case studies, we use PGMG in a ligand-based and structure-based drug de novo design. Overall, the flexibility and effectiveness make PGMG a useful tool to accelerate the drug discovery process.