CMOMO: a deep multi-objective optimization framework for constrained molecular multi-property optimization.

Abstract

Molecular optimization, aiming to identify molecules with improved properties from a huge chemical search space, is a critical step in drug development. This task is challenging due to the need to optimize multiple properties while adhering to stringent drug-like criteria. Recently, numerous effective artificial intelligence methods have been proposed for molecular optimization. However, most of them neglect the constraints in molecular optimization, thereby limiting the development of high-quality molecules that simultaneously satisfy property objectives and constraint compliance. To address this issue, we proposed a deep multi-objective optimization framework, termed CMOMO, for constrained molecular multi-property optimization. The proposed CMOMO divides the optimization process into two stages, which enables it to use a dynamic constraint handling strategy to balance multi-property optimization and constraint satisfaction. Besides, a latent vector fragmentation based evolutionary reproduction strategy is designed to generate promising molecules effectively. Experimental results on two benchmark tasks show that the proposed CMOMO outperforms five state-of-the-art methods to obtain more successfully optimized molecules with multiple desired properties and satisfying drug-like constraints. Moreover, the superiority of CMOMO is verified on two practical tasks, including a potential protein-ligand optimization task of 4LDE protein, which is the structure of $\beta $2-adrenoceptor GPCR receptor, and a potential inhibitor optimization task of glycogen synthase kinase-3$\beta $ target (GSK3$\beta $). Notably, CMOMO demonstrates a two-fold improvement in success rate for the GSK3$\beta $ optimization task, successfully identifying molecules with favorable bioactivity, drug-likeness, synthetic accessibility, and adherence to structural constraints.