Formação de complexos entre compostos híbridos pirrolbenzodiazepinas-cumarinas com DNA por estudos de docking molecular

Abstract

Compounds of the pirrolbenzodiazepine (PBD) family are known for their promising antitumor activity. Among these, the hybrids, those that have a portion PDB a chain spacer and another functional group, such as the coumarins of this work, have been extensively explored. It is also known that these compounds bind to DNA, but there is no structural data showing how it occurs. To overcome this lack of information molecular docking calculations were performed to study the formation of complexes between these PBD-hybrids and DNA. The compounds were modeled and the coordinates of complexes DNA-receptors with different ligands were obtained from the Protein Data Bank. The redocking served to validate the conditions of the experiments and the scores were used as the parameter to evaluate the complexes formed. The analysis of the intermolecular interactions, an essential knowledge for understanding the obtained structures were analyzed using high-resolution molecular imaging. The results of the in silico experiments showed the formation of complexes in the mixed-mode with the PBD ligand moiety intercalating between the DNA bases and the coumarin portion occupying the minor groove, and a preference for intercalation between GG bases. Moreover, it is possible to postulate that the complex becomes an adduct with the formation of a covalent bond between the intercalated portion PBD and a nucleotide base G. Finally, a correlation between the docking results and the biological activities of the studied compounds was established.