Discovery of tricin as a novel ADAMTS1 inhibitor via molecular docking and ADMET predictions for inhibiting cancer metastasis

Abstract Background: ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) plays a crucial role in extracellular matrix (ECM) remodeling, cancer metastasis, and regulation of the tumor microenvironment. As ADAMTS1 has been implicated in tumor-promoting mechanisms across various cancer types, its inhibition has shown potential as a therapeutic strategy for aggressive cancers. Methods: In this study, we employed molecular docking and pharmacokinetic profiling to identify potential small-molecule inhibitors of ADAMTS1. In total, 26 natural and synthetic compounds were screened against ADAMTS1 using AutoDock Vina, followed by absorption, distribution, metabolism, excretion, and toxicity (ADMET)predictions via SwissADME. The in vitromigratory ability of cancer cells was assessed by transwell migration assay. Protein-based biochemical assays such as Western blotting to investigate ADAMTS1-regulated pathway. Results: We identified tricin as the lead compound (binding energy: –10.93 kcal/mol), a natural product with high oral absorption and non-carcinogenic properties. Functional assays revealed that tricin, at non-toxic concentrations, significantly inhibited the migratory and adhesive abilities of various oral squamous cell carcinoma (OSCC) and clear cell renal cell carcinoma (ccRCC) cell lines by suppressing expression or activation of ADAMTS1 and its downstream effectors including epidermal growth factor receptor (EGFR), Src, and focal adhesion kinase (FAK). Conclusions: These findings provide a computational framework for identifying tricin as a potential ADAMTS1 inhibitor and support its validation as a therapeutic agent for treating cancer metastasis, particularly in cancer types with high ADAMTS1 expression.