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