De novo 3D molecular design with multiple properties and fragment-retention constraints is formulated as a constrained multi-objective optimization problem. Existing 3D diffusion models provide strong capabilities for generating novel molecules, but adapting them to new conditions and multi-objective optimization tasks remains difficult. We present Diffusion-based Evolutionary Molecular Optimization (DEMO), a framework that draws solely on the unconditional molecular prior of a frozen pretrained diffusion model to generate chemically valid 3D candidates, while evolutionary search handles conditional generation and constrained multi-objective optimization, without retraining or fine-tuning. DEMO performs crossover and mutation on intermediate diffusion states through an Evolutionary-Guided Diffusion (EGD) operator, combines 2D topology and 3D geometry in Structure-Aware Environmental Selection (SAES) to preserve structural diversity, and uses three cooperating populations to coordinate structural exploration, fragment-constraint satisfaction, and property optimization. Experimental results demonstrate that EGD outperforms task-specific conditional generators in property targeting; SAES preserves structural diversity while retaining competitive hypervolume in multi-objective optimization; and DEMO improves objective convergence and generates diverse feasible molecules under fragment constraints. These results show how evolutionary search can reuse existing diffusion models for diverse molecular design requirements.

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