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bioRxiv · 10.64898/2026.04.19.719462

A Unified Agent-Enabled Platform for Drug Repurposing across Molecular, Phenotypic, and Clinical Scales

Wang, C.·El Moussaoui, M.·Zhang, D.·Prabhakaraalva, P.·Merzliakov, S.·Zaman, N.·Chakraborty, G.·Huang, K.-l.
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Abstract

Drug repurposing offers an effective path to new therapies, yet existing computational approaches rely on a single line of evidence and are rarely validated across biological scales. We present LinkD, an integrated framework that unifies diffusion-based affinity prediction, proteome-wide selectivity scoring, phenotypic validation, and population-scale clinical evidence. LinkD-Bind predicts binding across 14,981 drugs and 20,385 human targets, ranking first in 8 of 9 BindingDB, Davis, and KIBA evaluations, with the largest gains under cold-start conditions. LinkD-Select recovers 95.3% of known drug-target pairs by combining selectivity scoring and molecular docking. LinkD-Pheno integrates drug-sensitivity and CRISPR dependency data across 960 cancer cell lines, identifying 34 novel drug-gene pairs and recovering [~]85% of known targets among the top 50 candidates. Across 11.5 million individuals from Mount Sinai and UK Biobank, LinkD-prioritized {beta}-blockers propranolol (HR 0.82) and carvedilol (HR 0.92) reduced 5-year prostate cancer incidence relative to metoprolol, corroborated by ADRB2 docking and LNCaP growth inhibition. LinkD-Agent, which can effectively orchestrate all evidence layers, is served on a publicly available web platform (https://linkd-agent.onrender.com/), enabling a wide range of users to derive new drug repurposing opportunities through natural language queries.

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Wang, C., El Moussaoui, M., Zhang, D., Prabhakaraalva, P., Merzliakov, S., Zaman, N., Chakraborty, G., Huang, K.-l.. 2026-04-22. A Unified Agent-Enabled Platform for Drug Repurposing across Molecular, Phenotypic, and Clinical Scales. https://doi.org/10.64898/2026.04.19.719462

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