Multi-objective fluorescent molecule design with a data-physics dual-driven generative framework

Abstract

Designing fluorescent small molecules with tailored optical and physicochemical properties requires navigating vast, underexplored chemical space while satisfying multiple objectives and constraints. Conventional generate-score-screen approaches become impractical under such realistic design specifications, owing to their low search efficiency, unreliable generalizability of machine-learning prediction, and the prohibitive cost of quantum chemical calculation. Here we present LUMOS, a data-and-physics driven framework for inverse design of fluorescent molecules. LUMOS couples generator and predictor within a shared latent representation, enabling direct specification-to-molecule design and efficient exploration. Moreover, LUMOS combines neural networks with a fast time-dependent density functional theory (TD-DFT) calculation workflow to build a suite of complementary predictors spanning different trade-offs in speed, accuracy, and generalizability, enabling reliable property prediction across diverse scenarios. Finally, LUMOS employs a property-guided diffusion model integrated with multi-objective evolutionary algorithms, enabling de novo design and molecular optimization under multiple objectives and constraints. Across comprehensive benchmarks, LUMOS consistently outperforms baseline models in terms of accuracy, generalizability and physical plausibility for fluorescence property prediction, and demonstrates superior performance in multi-objective scaffold- and fragment-level molecular optimization. Further validation using TD-DFT and molecular dynamics (MD) simulations demonstrates that LUMOS can generate valid fluorophores that meet various target specifications. Overall, these results establish LUMOS as a data-physics dual-driven framework for general fluorophore inverse design.