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Transforming growth factor β type 1 receptor (TGFβR1), a crucial serine-threonine kinase, is central to the TGFβ/Smad signaling pathway, governing cellular processes like growth, differentiation, apoptosis, and immune response. This pathway is closely linked to the epithelial–mesenchymal transition (EMT) process, which plays an important role in the metastasis of hepatocellular carcinoma (HCC). To date, only limited inhibitors targeting TGFβR1 have entered clinical trials, yet they encounter challenges, notably high toxicity, in clinical applications. Herein, an efficient virtual screening pipeline was developed. Eighty compounds were screened from a pool of over 17 million molecules based on docking scores and binding free energy. Four compounds were manually selected with the assistance of enhanced sampling method BPMD (binding pose metadynamics). The binding stability of these four compounds complexed with TGFβR1 was subsequently studied through long-timescale conventional molecular dynamics simulations. The three most promising compounds were subjected to in vitro bioactivity assays. Cpd272 demonstrated moderate inhibitory activity against TGFβR1, with an IC50 value of 1.57 ± 0.33 μM. Moreover, it exhibited cytotoxic effects on human hepatocellular carcinoma cell line Bel-7402. By shedding light on the binding mode of the receptor–ligand complexes, Cpd272 was identified as a hit compound featuring a novel urea-based scaffold capable of effectively inhibiting TGFβR1. [ABSTRACT FROM AUTHOR]

A thermodynamic and kinetic study of the dissolution properties of urea phosphate (UP) in water is performed using a Calvet type microcalorimeter. Calorimetric measurements reveal the dissolution is endothermic and the heat is perfectly proportional to the amount of UP dissolved, yielding an enthalpy of (33.755 ± 0.65) kJ/mol. By combining the enthalpy data of our measurements and literature, we derive the enthalpies of urea‐phosphoric acid adduct reaction, formation of solid UP and UP dissociation. Dissolution kinetics parameters are estimated using the collected dynamic calorimetric data that are well represented with quasi‐second‐order kinetic model, giving an activation energy of (16.7 ± 2.7) kJ/mol. Thermodynamic modeling of the pH difference between UP and phosphoric acid solutions shows the degree of UP dissociation decreases from 74% to 42% when UP molality increases from 0.02 to 1 mol/kg. Furthermore, the species molality distributions in UP solutions are calculated based on mass balance and the dissociation equilibrium relations considered. [ABSTRACT FROM AUTHOR]