Revisiting colchicine pharmacology: structural and pharmacokinetic insights into GLP-1 receptor engagement

Abstract

Colchicine is a long-established anti-inflammatory agent primarily recognized for its microtubule-disrupting properties. Beyond its classical mechanism of action, potential interactions with alternative molecular targets remain incompletely understood. Given the growing relevance of glucagon-like peptide-1 receptor (GLP-1R) signaling in cardiometabolic regulation, this study aimed to computationally evaluate whether colchicine demonstrates structural compatibility with GLP-1R interaction domains. Danuglipron, a small-molecule GLP-1R agonist, was used as a reference compound. Molecular docking simulations were conducted using CB-Dock2 (Vina-based scoring) with the GLP-1 receptor structure (PDB ID: 6X1A). Binding energies, interacting residues within defined distance thresholds (≤4 Å and ≤6.5 Å), and potential polar contacts (≤3.5 Å) were examined. Ligand efficiency values were calculated to normalize binding energy to molecular size. Physicochemical properties were assessed using SwissADME, and pharmacokinetic and toxicity predictions were obtained from ADMETlab 3.0. Danuglipron demonstrated a binding energy of −12.8 kcal/mol within the canonical transmembrane cavity of GLP-1R. Colchicine exhibited a docking score of −9.3 kcal/mol and localized to a spatially distinct region of the receptor. SwissADME analysis indicated that both molecules fall within acceptable physicochemical space for oral drug candidates, with high predicted gastrointestinal absorption and identical bioavailability scores (0.55). The computational findings suggest that colchicine can form structured interactions with GLP-1R, although its binding mode differs from that of a canonical orthosteric agonist. These results do not establish functional receptor modulation but provide a structural basis for further experimental investigation into potential non-classical receptor interactions.