End-to-End Reverse Screening Identifies Protein Targets of Small Molecules Using HelixFold3

• URL: http://arxiv.org/abs/2601.13693v1
• Date: Tue, 20 Jan 2026 07:45:53 GMT
• Title: End-to-End Reverse Screening Identifies Protein Targets of Small Molecules Using HelixFold3
• Authors: Shengjie Xu, Xianbin Ye, Mengran Zhu, Xiaonan Zhang, Shanzhuo Zhang, Xiaomin Fang,
• Abstract summary: We present an end-to-end reverse screening strategy leveraging HelixFold3, a high-accuracy biomolecular structure prediction model.<n>Compared with conventional reverse docking, our method improves screening accuracy and demonstrates enhanced structural fidelity, binding-site precision, and target prioritization.
• Score: 5.391814889850861
• License: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Abstract: Identifying protein targets for small molecules, or reverse screening, is essential for understanding drug action, guiding compound repurposing, predicting off-target effects, and elucidating the molecular mechanisms of bioactive compounds. Despite its critical role, reverse screening remains challenging because accurately capturing interactions between a small molecule and structurally diverse proteins is inherently complex, and conventional step-wise workflows often propagate errors across decoupled steps such as target structure modeling, pocket identification, docking, and scoring. Here, we present an end-to-end reverse screening strategy leveraging HelixFold3, a high-accuracy biomolecular structure prediction model akin to AlphaFold3, which simultaneously models the folding of proteins from a protein library and the docking of small-molecule ligands within a unified framework. We validate this approach on a diverse and representative set of approximately one hundred small molecules. Compared with conventional reverse docking, our method improves screening accuracy and demonstrates enhanced structural fidelity, binding-site precision, and target prioritization. By systematically linking small molecules to their protein targets, this framework establishes a scalable and straightforward platform for dissecting molecular mechanisms, exploring off-target interactions, and supporting rational drug discovery.

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