2. Academic Validation
  3. Computational discovery and repurposing of chloramphenicol succinate as a potent P2Y14 receptor antagonist for inflammatory bowel disease therapy

Computational discovery and repurposing of chloramphenicol succinate as a potent P2Y14 receptor antagonist for inflammatory bowel disease therapy

  • J Adv Res. 2025 Aug 22:S2090-1232(25)00650-2. doi: 10.1016/j.jare.2025.08.035.
Sheng Tian 1,  Kai Wang 2,  Chunxiao Liu 3,  Xinyu Chen 2,  Xiaotian Kong 4,  Zhoudong Zhang 2,  Gui Shao 2,  Shufan Ren 2,  Qinghua Hu 5,  Huanqiu Li 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou 215123, China. Electronic address: [email protected].
  • 2 College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou 215123, China.
  • 3 School of Pharmacy and School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
  • 4 College of Chemistry and Life Science, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing University of Technology, Beijing 100124, China. Electronic address: [email protected].
  • 5 School of Pharmacy and School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
  • 6 College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou 215123, China. Electronic address: [email protected].
PMID: 40850683 DOI: 10.1016/j.jare.2025.08.035
Abstract

Introduction: The P2Y14 receptor (P2Y14R), a Gi-coupled receptor activated by UDP-glucose, plays a critical role in inflammatory responses and immune regulation. Existing P2Y14R antagonists face limitations such as poor bioavailability and structural homogeneity, hindering therapeutic development for inflammatory bowel disease (IBD). Drug repurposing offers a promising strategy to bypass traditional drug discovery challenges by leveraging approved drugs with established safety profiles.

Objectives: This study aimed to computationally identify FDA-approved or experimental drugs as novel P2Y14R antagonists and validate their therapeutic potential for IBD treatment.

Methods: A multi-step computational pipeline integrated structure-based virtual screening (SBVS) of DrugBank drug compounds, molecular docking (Glide XP/AutoDock Vina), molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Top candidates underwent in vitro P2Y14R antagonism assays and cytotoxicity testing. In vivo efficacy was evaluated in a DSS-induced murine colitis model.

Results: Chloramphenicol succinate (DB07565), an Antibiotic, emerged as a potent P2Y14R antagonist with nanomolar efficacy (IC50 = 1.585 nM) and minimal cytotoxicity. MD simulations revealed strong interactions with conserved residues (K77, Y102, H184, K277), yielding a binding affinity (ΔGbind = -54.04 kcal/mol) superior to reference compounds. In vivo, DB07565 alleviated colitis symptoms, reduced colon shortening, and restored gut barrier integrity by enhancing tight junction protein expression (Claudin-1, ZO-1, Occludin).

Conclusion: This study demonstrates that computational repurposing successfully identifies DB07565 as a high-affinity P2Y14R antagonist with therapeutic efficacy in IBD. Its established safety, oral stability, and optimized ADME/T properties position it as a clinically translatable candidate, underscoring the value of integrating SBVS and drug repurposing for accelerating anti-inflammatory drug discovery.

Keywords

Drug repurposing approache; IBD treatment; Molecular dynamic simulation; P2Y14R antagonists; SBVS.

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