RESUMO
A set of ninety-eight B-RafV600E inhibitors was used for the development of a molecular docking based QSAR model using linear and non-linear regression models. The integration of docking scores and key interaction profiles significantly improved the accuracy of the QSAR models, providing reasonable statistical parameters (Rtrain2 = 0.935, Rtest2 = 0.728 and QCV2 = 0.905). The established MD-SVR (molecular docking based SMV regression) model as well as model screening of a natural product database was carried out and two natural products (quercetin and myricetin) with good prediction activities were biologically evaluated. Both compounds exhibited promising B-RafV600E inhibitory activities (ICQuercetin50 = 7.59 µM and ICMyricetin50 = 1.56 µM), suggesting a high reliability and good applicability of the established MD-SVR model in the future development of B-RafV600E inhibitors with high efficacy.
RESUMO
Recent researches have discovered that MDM2 (murine double minute 2, or HDM2 for the human congener) protein is the main negative regulator of p53, which is an attractive therapeutic target in oncology because its tumor-suppressor activity which can be stimulated to eradicate tumor cells. Inhibiting the p53-MDM2 interaction is a promising approach for activating p53, because this association is well characterized at the structural and biological levels. A number of drug screening approaches and technologies have been used to identity novel inhibitors of the p53-MDM2 interaction. This review will detail the development history of MDM2 protein and the p53-MDM2 interaction, the major classes of novel small-molecular p53-MDM2 binding inhibitors, key medicinal action with the protein-protein interaction and in vitro or in vivo biological activities.
