Desenvolvimento de um modelo emp?rico de predi??o da seletividade e da atividade de inibidores da Shp2 utilizando o m?todo semi-emp?rico PM7

• Autor(a) principal: Rocha, Sheisi Fonseca Leite da Silva
• Data de Publicação: 2019
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRRJ
• Texto Completo: https://tede.ufrrj.br/jspui/handle/jspui/5153
• topic: Shp2; Seletividade; Docagem; PM7; Efeito eletrol?tico; Selectivity; Docking; Electrolytic effect; Qu?mica

Shp2, along with Shp1, forms a small family of protein tyrosine phosphatases. Studies suggest that although inhibition of Shp2 is advantageous for the treatment of some types of cancer, inhibition of Shp1 may have the opposite effect because it acts as a tumor suppressor. In this way, we sought to develop an in silico methodology capable of identifying more selective Shp2 inhibitors. In this work, we showed that in spite of the thermodynamic complexity involved in the enzyme/inhibitor interaction, it was possible to correlate the selectivity of two series (76 compounds) with the difference of the enthalpy of interaction calculated in both enzymes. The interaction profile of the inhibitors with Shp2 and Shp1 were initially obtained by molecular docking. After the refinement of the geometries of the enzyme / inhibitor complexes with the semi-empirical molecular orbital PM7 method, the enthalpy values of the interaction were obtained. For the series 1, composed of 52 selective inhibitors of Shp2, we demonstrated that the enthalpy of interaction can be used as a reliable criterion for the identification of selective inhibitors for Shp2, since it was significantly more favorable for Shp2 than for Shp1 with a confidence level of 99%. For series 2, composed of 24 compounds, a satisfactory correlation (R = 0.70) could be obtained between the selectivity and the relative percentage difference of the calculated enthalpies of interaction in both enzymes. Another objective of this work was to construct a model of prediction of the activity of inhibitors of Shp2 using as empirical basis the series 1 to validate it later with the series 2. Due to the presence of negatively charged inhibitors within the series, it was necessary to consider the electrolytic effect, correcting the experimental values of inhibitory activity, since such data refer to formal concentrations and the thermodynamic constant involves effective concentrations. For this it was necessary to calculate the ionic strength of the reaction medium and to estimate the activity coefficients of the species involved in the enzyme /inhibitor dissociation equilibrium through the Guntelberg equation. The construction of the model was based on literature proposals on the use of thermodynamic cycles to calculate the free energy of interaction between ligands and enzymes. In this sense, terms related to the enthalpy of interaction of the enzyme / inhibitor complex, the energy of solvation of the ligand and the entropic losses due to rotational restrictions were obtained after their interaction with the enzyme. These terms were correlated through linear multiple regression with experimental data of inhibition. In this way it was possible to develop a prediction model of the activity of inhibitors of Shp2 with good correlation with experimental data (R = 0.83). This model was validated satisfactorily (R = 0.73) with series 2 and used in the prediction of the relative activity of new compounds.