Métodos computacionais aplicados na busca por novos fármacos contra alvos moleculares em hepatite C, câncer e leishmaniose

Abstract

The computational approach in the planning and development of new drugs is related to the molecular understanding of the target under study. The understanding of protein-ligand interactions serves as a guide to plan and develop potential binders. From this point of view, this work was accomplished with the use of computational methods in molecular targets involved in three diseases. In the first part, the in silico study was applied to the enzymes NS3-4A and NS5B pertaining to the hepatitis C virus. The energy decomposition and the types of interactions when compared to the drug telaprevir suggest that three ligands have better potential to inhibit the NS3-4A protein. In the understanding of the molecular behavior, the study with the NS5B enzyme in the presence and absence of Mg2+ ions showed that the interaction this enzyme with the drug sofosbuvir is more effective in the presence of Mg2+ in the active site. This results was applied in the search for new ligands of NS5B where a ligand with better interaction than the drug sofosbuvir was found. In the second part, the enzyme kinase PKC δ present in the metabolic pathway of head and neck cancer had its 3D structure predicted by homology modeling. The molecular docking of the PKC δ model was performed with 10 molecules present in the latex of Euforbia tirucalli L. due to its anticancer action. The results demonstrated that eufol, β-sitosterol and taraxasterol molecules may be promising candidates for the development of new anticancer drugs in head and neck tumors. In the third part, the study was performed with cysteine proteases of Llacys1, T. cruzi and cruzain of Leishmania amazonensis, respectively, with 3 benzophenone derivatives. The results demonstrate that the interactions of benzophenone derivatives with Llacys1 and cruzain occur at the same binding site on the surface of the proteins, suggesting that two benzophenone are promising in inhibiting cysteine proteases. Therefore, the results of these studies showed the power of computational chemistry techniques in the understanding of phenomena at the molecular leves and brought new perspectives for the treatment of hepatitis C, head and neck cancers and leishmaniasis.