Activation of the phosphatidylinositol 3-kinase α (PI3Kα) is commonly observed in human cancer and is critical for tumor progression, which has made PI3Kα an attractive target for anticancer drug discovery. To systematically investigate the binding mode of A-66S, a new selective PI3Kα inhibitor for PI3Kα, molecular docking, molecular dynamics simulation and ensuing energetic analysis were performed. The binding free energy between PI3Kα and A-66S is -11.27 kcal•mol⁻¹ using MMPBSA method, while -14.67 kcal•mol⁻¹ using MMGBSA method, which is beneficial for the binding, and the van der Waals/hydrophobic and electrostatic interactions are critical for the binding. The conserved hydrophobic adenine region of PI3Kα made up of Met772, Pro778, Ile800, Tyr836, Ile848, Val850, Val851, Met922, Phe930 and Ile932 accommodates the flat 2-tert-butyl-4'-methyl-4,5'-bithiazol moiety of A-66S, and the NH of Val851 forms a hydrogen with the nitrogen atom embedded in the aminothiazole ring of A-66S. The (S)-pyrrolidine carboxamide urea moiety especially extends toward the region of the binding site wall (Ser854-Gln859) defined by the C-terminal lobe, and has three hydrogen-bond arms with the backbone of Ser854 and the side chain of Gln859. Notably the interaction between the non-conserved residue Gln859 and A-66S is responsible for the selectivity profile of A-66S. The binding mode of A-66S for PI3Kα presented in this study should aid in the design of a new highly selective PI3Kα inhibitor.
The dissociation constants (pK a ) of dalbergin and nordalbergin were measured at 298.2 K using ultraviolet (UV) spectroscopy method. The solubilities of dalbergin and nordalbergin in water, methanol, propanone, ethyl ethanoate, trichloromethane, and hexane have been determined by the UV spectrophotometric method from 283.2 to 308.2 K at atmospheric pressure. The experimental solubility values were correlated with a modified Apelblat equation, λh model, and ideal model. The pK a value of dalbergin is 8.91 ± 0.12, and the pK a1 and pK a2 values of nordalbergin are 7.31 ± 0.29 and 9.79 ± 0.39, respectively. The solubilities of dalbergin and nordalbergin in six solvents increase with an increase in temperature. The solubility order of dalbergin in six pure solvents was trichloromethane > propanone > ethyl ethanoate > methanol > hexane > water, whereas that of nordalbergin was propanone > methanol > ethyl ethanoate > trichloromethane > water > hexane. A comparison of the solubility of dalbergin with that of nordalbergin shows that the 7-methoxyl moiety of dalbergin leads to a significantly higher solubility in trichloromethane and hexane, a little higher solubility in ethyl ethanoate, an approximately equal solubility in propanone, and a little lower solubility in methanol and water (exception 283.2 K). For dalbergin, the modified Apelblat equation shows the best correlation for all solvents, and for nordalbergin, correlation results by three models are similar.
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