Bioinformática estrutural aplicada a busca por novos compostos contra os alvos moleculares p53- Y220C, MDM2, BIRC7, em câncer

Abstract

Advances in knowledge of the cancer cell genome in recent years have driven the search for new therapeutic agents with optimized pharmacodynamic and pharmacokinetic properties. Cancer has a high incidence and mortality in countries around the world. The therapies available are still not effective in treating many types of cancer, especially when they are in an advanced stage. In addition, many treatments cause a series of debilitating side effects that alter people's quality of life. The occurrence of changes in the molecular targets, P53-Y220C (Cellular tumor antigen p53-y220c), MDM2 (E3 ubiquitin-protein ligase Mdm2), BIRC7 (Baculoviral IAP repeat-containing protein 7), are important for the establishment of cancer, crucial role they play in regulating the apoptotic pathway. In this context, the present work aimed to identify potential ligands for the molecular targets p53-y220C, MDM2 and BIRC7, based on in silico analyzes. Through the molecular docking technique it was possible to calculate the interaction energy between the binding molecules and the respective molecular targets for the selection of compounds that form more stable complexes, with less binding energy during the interaction process. The bioisosterism technique was used to generate molecules analogous to the ligands established as a control for molecular docking assays from the selection of functional groups that present less favorable interaction with their respective molecular targets. For the ligand code RZH derived from indole, crystallized with the protein p53-y220C code pdb: 5AOI, the molecular fragments N1 and N2 were selected for bioisosteric substitution. For the G13 ligand crystallized with the BIRC7 protein, code pdb: 3F7I, the molecular fragments N2, N7 and N23 were selected for bioisosteric substitution. For the MDM2 protein, ligands were selected from the ZINC database for molecular docking assays. According to results obtained during molecular docking calculations, the compounds Bio 011 N1 (-7.2 kcal.mol-1), Bio 009 N1 (-7.0 kcal.mol-1), Bio 004 N2 (- 7.0 kcal.mol-1), Bio 002 N2 (-6.9 kcal.mol-1) Bio 003 N2 (-6.9 kcal.mol-1) and Bio 003 N2 (-6. kcal.mol-1) are promising candidates for restoring the function of the p53 protein with the Y220C alteration. Compounds ZINC49525064 (-7.9 kcal.mol-1), ZINC49524869 (-7.9 kcal.mol-1), ZINC37307305 (-7.9 kcal.mol-1), ZINC37307202 (-7.9 kcal.mol-1) are promising candidates for inhibiting the MDM2 protein. And the compounds BBio 003 (-9.7 kcal.mol-1), BBio 001 (-9.5 kcal.mol-1), BBio 002 (-8.1 kcal.mol-1), BBio 007 (-8.1 kcal.mol-1) BBio 008 (-7.9 kcal.mol-1) are promising candidates to inhibit protein to BIRC7. All the compounds identified showed physical and chemical parameters that respect the rules of the five of Lipinski (RO5) and can be administered orally. Theoretically these substances may contribute to the development of new experimental research and clinical trials.