A New Insight into Toxicity of Colchicine Analogues by Molecular Docking Analysis Based on Intestinal Tight Junction Protein ZO-1

Abstract

Colchicine (COL) is a well-known plant alkaloid long used for medical purposes due to the selective anti-inflammatory effect on acute gouty arthritis. It is also a kind of mitosis toxin with strong inhibitory effects of cell division and is therefore being applied to the treatment of various cancers. However, this product shows a variety of adverse effects that are significantly correlated with the dosage and have attracted much attention. For the first time, the present work obtained a new insight into the gastrointestinal toxicity of colchicine analogues by molecular docking analysis, which was based on the 3D structure of intestinal tight junction protein ZO-1 and the ligand library containing dozens of small-molecule compounds with the basic skeleton of COL and its metabolites. The binding energy and mode of protein–ligand interaction were investigated to better understand the structure–toxicity relationships of COL analogues and the mechanism of action as well. Cluster analysis clearly demonstrated the strong correlation between the binding energy and toxicity of ligand molecules. The interaction mode further revealed that the hydrogen bonding (via the C-7 amide or C-9 carbonyl group) and hydrophobic effect (at ring A or C) were both responsible for ZO-1-related gastrointestinal toxicity of COL analogues, while metabolic transformation via phase I and/or phase II reaction would significantly attenuate the gastrointestinal toxicity of colchicine, indicating an effective detoxication pathway through metabolism.

Protective effect of sialyllactose on the intestinal epithelium in weaned pigs upon enterotoxigenic Escherichia coli challenge

“…Zonula occludens-1 (ZO-1) is one of the most important proteins of TJP, which is indispensable in the penetration between adjacent cells, signal transduction, gene transcription, cell proliferation, and differentiation. 38–41 In this study, the ETEC challenge decreased the abundance of ZO-1 protein in the jejunal and ileal epithelium. However, dietary SL not only elevated the abundance of jejunal ZO-1 protein in the non-challenged pigs but also elevated the abundance of ileal ZO-1 protein in the ETEC-challenged pigs.…”

Molecular Docking Analysis of PVDF Membrane Against Human Erα, EGFR, CDK2, mTOR, and HSP90 Proteins

“…The molecular docking approach is used to model the interaction between a molecule and a protein at the atomic level. This situation allows us to characterize the behavior of molecules in the binding site of target proteins and elucidate fundamental biochemical processes [15]. In this study, the interaction between the hydrophobic PVDF molecule and Erα, EGFR, CDK2, mTOR, and HSP90 proteins have been evaluated by molecular docking.…”

Insect cell‐derived human CD200‐Fc increases zonula occludens‐1 tight junction protein in urothelial carcinoma cells

“…2021; Liu et al . 2022). In epithelial cells, TJs can function in an adhesive manner and prevent cell dissociation (Hollande et al .…”

“…Therefore, ZO‐1 is used as an indicator and marker to observe the permeability and barrier function of various tissues (Liu et al . 2022; Brunner et al . 2023).…”