Reading the Cell, Designing the Cure: Perturbation-Conditioned Molecular Diffusion for Function-Oriented Drug Design
This paper formalizes Transcriptome-based Drug Design (TBDD) as a generative inverse problem, proposing a multi-resolution transcriptome-guided diffusion framework named CURE. It addresses challenges like domain gap and signal sparsity with a specialized feature extractor, outperforming baselines in structural quality and functional consistency.
[2605.15243] Reading the Cell, Designing the Cure: Perturbation-Conditioned Molecular Diffusion for Function-Oriented Drug Design
[Submitted on 14 May 2026]
Title:Reading the Cell, Designing the Cure: Perturbation-Conditioned Molecular Diffusion for Function-Oriented Drug Design
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Abstract:When reliable target structures are unavailable at scale or phenotypes arise from dysregulated pathways, transcriptomic perturbations provide a system-level functional readout for drug action. In this work, we formalize \emph{Transcriptome-based Drug Design (TBDD)} as a generative inverse problem: designing drug molecules conditioned on desired transcriptomic state transitions. We analyze the inherently ill-posed nature of this task, which is further complicated by the profound domain gap between biology and chemistry and by the sparsity of transcriptomic signals. To address these challenges, we propose \textbf{\themodel{}} (A \textbf{C}ell\textbf{U}lar \textbf{R}esponse \textbf{E}ngine), a multi-resolution transcriptome-guided diffusion framework. \themodel{} features a specialized \textbf{Transcriptome Perturbation Functional Feature Extractor (TFE)} that (1) distills function-oriented perturbation embeddings from pre/post states, (2) aligns these signatures to dual chemical views to bridge the cross-modal gap, and (3) performs heterogeneity-aware aggregation to extract robust state-specific signals from noisy transcriptomic data. Extensive evaluations on both standard benchmarks and rigorous out-of-distribution protocols demonstrate that \themodel{} consistently outperforms strong baselines in structural quality and functional consistency. Furthermore, we validate its practical utility via a zero-shot gene-inhibitor design task, highlighting the potential of phenotype-driven generative discovery.
Subjects:
Machine Learning (cs.LG); Artificial Intelligence (cs.AI); Biomolecules (q-bio.BM); Molecular Networks (q-bio.MN); Quantitative Methods (q-bio.QM)
Cite as: arXiv:2605.15243 [cs.LG]
(or arXiv:2605.15243v1 [cs.LG] for this version)
https://doi.org/10.48550/arXiv.2605.15243
arXiv-issued DOI via DataCite (pending registration)
Submission history
From: Ziyu Xu [view email] [v1] Thu, 14 May 2026 07:17:10 UTC (1,747 KB)
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