Molecular Recognition and Inhibition Mechanism of Benzopyrone Compounds With Skp2 Proteins

The protein aggregate of S-phase kinase-associated protein 2 (Skp2) complex with Skp1 plays an important role in regulating the growth cycle of cancer cells. The benzopyrone inhibitor BPC can effectively hinder the formation of Skp1-Skp2 complex. The simulation system was determined through bioinformatics statistical analyses of the available Skp1-Skp2 crystal complex, and the missing structural unit was mended via homology modeling. Then, the Skp1-Skp2-BPC complex model was obtained by using molecular docking and adopted for subsequent molecular dynamics (MD) simulations. Computational results show that hydrophobic interaction is the major driving force impelling BPC to specially bind to the pocket composed of W109, D110, L117, I120, R138 and W139 of Skp2. The calculated free energy values agree well with the experimental data. After the association of Skp2 with BPC, the hydrogen bond network of active pocket moderately strengthens and the number of solvated water molecule around the pocket decrease significantly, which leads to the reduction of Skp1-Skp2 systemic stability. According to the analyses of conformational clustering and motion characteristics, the motion of Skp1 becomes more vigorous after Skp1-Skp2 binding with BPC, which may be one of the main inhibitory mechanisms of BPC. This work provides a theoretical basis for deeply understanding the structure-function relationships of Skp1-Skp2 and rationally designing novel anticancer inhibitors based on receptor structure.