Estudos teóricos da PP5-Mg2+ como alvo promissor para o tratamento do câncer: uma abordagem de modelagem molecular

Abstract

Molecular modeling is indispensable in the development of more efficient, potent and safe drugs. In this line, for the accomplishment of this work, diverse methods of molecular mechanics and quantum mechanics were applied, in order to interpret the molecular mechanism involved in the drug-receptor interaction, responsible for the biological activity. As therapeutic target, PP5 was chosen, being this directly related to the pathological frame of cancer. This disease, despite all scientific and technological advances, is still associated with the possibility of physical and emotional suffering, and requires of its victims a very aggressive treatment. In view of these circumstances, it is necessary to investigate the mechanism of inhibition of PP5. Since this enzyme affects several cellular functions, such as proliferation, migration, differentiation and repair of DNA damage. Thus, PP5 can be considered an innovative, challenging and promising therapeutic target for the treatment of cancer. Therefore, the use of MM will be important to evaluate the interactions that are more favorable for the inhibitory activity of PP5, which help in the proposal of new bioactive compounds. Thus, the computational methods used in this work were: classical molecular dynamics simulation, QM / MM methods and AIM calculations. The results showed that Arg275, Asn303, His304, His352, Arg400, His427, Val429, Tyr452 and Phe446 contributed favorably to a good accommodation of the Cantharidin-like inhibitors at the PP5 site, and the potentiality of the compounds is related to the coordination that they perform with the Mg2+ metals. These results have brought an understanding of how the inhibition mechanism in PP5 takes place, potentially allowing the planning of drugs for the treatment of cancer.