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bioRxiv · 10.1101/2025.02.19.638723

MolGene-E: Inverse Molecular Design to Modulate Single Cell Transcriptomics

Ohlan, R.·Murugan, R.·Xie, L.·Mottaqi, M.·Zhang, S.
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Abstract

Designing drugs that can restore a diseased cell to its healthy state is an emerging approach in systems pharmacology to address medical needs that conventional target-based drug discovery paradigms have failed to meet. Single-cell transcriptomics can comprehensively map the differences between diseased and healthy cellular states, making it a valuable technique for systems pharmacology. However, single-cell omics data is noisy, heterogeneous, scarce, and high-dimensional. As a result, no machine learning methods currently exist to use single-cell omics data to design new drug molecules. We have developed a new deep generative framework named MolGene-E to tackle this challenge. MolGene-E combines two novel models: 1) a cross-modal model that can harmonize and denoise chemical-perturbed bulk and single-cell transcriptomics data, and 2) a contrastive learning-based generative model that can generate new molecules based on the transcriptomics data. MolGene-E consistently outper-forms baseline methods in generating high-quality, hit-like molecules on gene expression profiles from two evaluation settings: CRISPR knock-out perturbation profiles from L1000toRNAseq dataset, and single-cell gene expression profiles from Sciplex-3 dataset, both in zero-shot molecule generation setting. This superior performance is demonstrated across diverse de novo molecule generation metrics. Extensive evaluations demonstrate that MolGene-E achieves state-of-the-art performance for zero-shot molecular generations. This makes MolGene-E a potentially powerful new tool for drug discovery.

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Ohlan, R., Murugan, R., Xie, L., Mottaqi, M., Zhang, S.. 2025-02-24. MolGene-E: Inverse Molecular Design to Modulate Single Cell Transcriptomics. https://doi.org/10.1101/2025.02.19.638723

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