PhenoMoler: Phenotype-Guided Molecular Optimization via Chemistry Large Language Model

• URL: http://arxiv.org/abs/2509.21424v1
• Date: Thu, 25 Sep 2025 09:37:19 GMT
• Title: PhenoMoler: Phenotype-Guided Molecular Optimization via Chemistry Large Language Model
• Authors: Ran Song, Hui Liu,
• Abstract summary: PhenoMoler generates chemically valid, novel, and diverse molecules aligned with desired phenotypic profiles.<n>Compared to FDA-approved drugs, the generated compounds exhibit comparable or enhanced drug-likeness (QED), optimized physicochemical properties, and superior binding affinity to key cancer targets.
• Score: 9.301996807475282
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: Current molecular generative models primarily focus on improving drug-target binding affinity and specificity, often neglecting the system-level phenotypic effects elicited by compounds. Transcriptional profiles, as molecule-level readouts of drug-induced phenotypic shifts, offer a powerful opportunity to guide molecular design in a phenotype-aware manner. We present PhenoMoler, a phenotype-guided molecular generation framework that integrates a chemistry large language model with expression profiles to enable biologically informed drug design. By conditioning the generation on drug-induced differential expression signatures, PhenoMoler explicitly links transcriptional responses to chemical structure. By selectively masking and reconstructing specific substructures-scaffolds, side chains, or linkers-PhenoMoler supports fine-grained, controllable molecular optimization. Extensive experiments demonstrate that PhenoMoler generates chemically valid, novel, and diverse molecules aligned with desired phenotypic profiles. Compared to FDA-approved drugs, the generated compounds exhibit comparable or enhanced drug-likeness (QED), optimized physicochemical properties, and superior binding affinity to key cancer targets. These findings highlight PhenoMoler's potential for phenotype-guided and structure-controllable molecular optimization.

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