Estudos in silico aplicados na busca de inibidores da tirosina quinase para o tratamento de tumores do estroma gastrointestinal (GIST)

Abstract

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract, and the standard diagnosis is the expression of CD117 (c-kit). Inoperable or metastatic tumors are treated with imatinib mesylate (Glivec®), a drug with a molecular target that acts as a multiple competitive tyrosine kinase inhibitor. Cellular mutations make the drugs ineffective through resistance mechanisms, and, therefore, new drugs or new molecular targets must be researched. Computational tools applied to medicinal chemistry, such as, the Development of New Computer-Aided Drugs, are strategies for the expansion of alternatives to established therapies. In this paper, a research was performed in the Sistemat-X database, in order to find new compounds that structurally resemble the drugs currently used. The 169 structures obtained were submitted to the Docking process, against the tyrosine kinase enzyme (Code PDB: 3G0E), using the program iGEMDOCK v 2.0. The results indicated that 17 compounds act on the same active site as sunitinib and showed the lowest interaction energies, 139 compounds act on another binding site, close to the one of sunitinib, but with higher energies, and 13 compounds act on other protein sites, and did not have their binding energies calculated. The 10 best docking results were subjected to molecular dynamics calculations using the GROMACS 5.0 program. The results indicated that all compounds are stable at the active site, as well as sunitinib. The calculation of ADMET properties indicated that only compound 121 has the desirable properties of a drug.