Integrated framework of fragment-based method and generative model for lead drug molecules discovery

Generative models have proven valuable in generating novel lead molecules with drug-like properties. However, beyond generating drug-like molecules, the generative model should also be able to create drug molecules with structural properties and pharmacophores to modulate a specific disease. The molecular generation process should also address the multi-objective optimization challenge of producing molecules with the desired efficacy and minimal side effects. This may entail the generation of a diverse pool of molecules with the desired structural properties and pharmacophore, which would offer diverse options and paths to developing potential new drug candidates by prioritizing molecules that balance the desired properties that can cater to the needs of different individuals. Achieving this requires a generative model learning a large dataset of molecular instances with the desired chemical/structural properties. However, large sets of drug molecules are not readily available for many diseases as there are few known drug molecular instances for treating any disease. To address this challenge, this paper presents an in silico molecular generative framework aided by fragment-based molecules’ synthesis for generating a pool of lead molecular instances possessing structural properties and pharmacophores to treat a disease of interest. The operation of the framework is explored using Hypertension as the disease of interest and beta-blocker as the reference hypertension drug to be generated. We generated over 123 beta-blocker-like molecules and further virtual-screened them for drug-likeness, docking probability, scaffold diversity, electrostatic complementarity, and synthesis accessibility to arrive at the final lead beta-blocker-like molecules. © 2025 The Author(s)