Computational discovery and repurposing of chloramphenicol succinate as a potent P2Yreceptor antagonist for inflammatory bowel disease therapy.

Abstract

INTRODUCTION: The P2Yreceptor (P2YR), a Gi-coupled receptor activated by UDP-glucose, plays a critical role in inflammatory responses and immune regulation. Existing P2YR 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 P2YR 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 P2YR 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 P2YR antagonist with nanomolar efficacy (IC = 1.585 nM) and minimal cytotoxicity. MD simulations revealed strong interactions with conserved residues (K77, Y102, H184, K277), yielding a binding affinity (ΔG = -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 P2YR 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.