Diffusion-based Evolutionary Optimization for 3D Multi-Objective Molecular Generation

Abstract

Optimizing conflicting molecular properties while strictly adhering to complex 3D structural constraints constitutes a challenging Constrained Multi-Objective Optimization Problem (CMOP). Traditional Evolutionary Algorithms (EAs) destroy chemical valency in 3D space, whereas 3D diffusion models act as rigid generators requiring costly retraining for novel objectives. To bridge this gap, we propose a progressive algorithmic suite. First, we introduce the Evolutionary-Guided Diffusion (EGD) operator, which executes crossover and mutation at an optimally calibrated noise level, leveraging a pre-trained denoising network to project chimeric states back onto the valid chemical manifold. Second, to combat the severe loss of molecular structural diversity inherent in traditional EMO frameworks, we design a Structure-Aware Environmental Selection (SAES) mechanism that explicitly enforces structural distinctiveness. Finally, synergizing EGD and SAES, we develop the Diffusion-based Evolutionary Molecular Optimization (DEMO) framework for CMOPs. To safely navigate disjoint feasible regions, DEMO employs a tri-population architecture with distinct goals: exploring novel chemical scaffolds, refining partially assembled intermediates, and fine-tuning perfectly feasible elite molecules. Extensive experiments across single-property targeting, unconstrained MOPs, multi-fragment CMOPs, and 3D protein-ligand docking demonstrate that our method comprehensively outperforms state-of-the-art baselines and traditional EMO frameworks. Operating entirely zero-shot, this suite consistently discovers highly diverse, chemically valid Pareto frontiers.