Padronização do método de virtual screening no banco de dados Zinc para obtenção de moléculas antagonistas de integrinas da família β1 visando ao desenho de novos fármacos antiinflamatórios

Abstract

Integrins are transmembrane cell surface proteins, which have the properties of adhesion, migrations and proliferation of immune cells by recognizing, mainly, binding sites in extracellular matrix proteins. The integrins are heterodimeric molecules composed of α and β subunits, which comprise so far 24 subtypes formed out of 18 different α and 8 different β chains. The integrins are important mediators of inflammatory processes, due to their properties of adhesion and migration. Inhibitors have been searched to develop new drugs with pharmacological potential. Three integrins (α4β1, α5β1 and αVβ1) have been studied as receptors of different inhibitors by Molecular Docking and Virtual screening techniques. These integrins were chosen because of their fibronectin interactions. The crystal structure of α4, α5, αV and β1 were obtained on PDB database (Crystal id: 3V4P, 3VI3, 1JV2 and 3VI3 respectively). The complexes α4β1, α5β1 and αVβ1 were created by aligning the monomers to their respective partner. The molecules used as ligands were taken from Zinc Database, which has approximately 22 million molecules. Because of this great number, only the ligands that follow Lipinski’s rules on the Clean Leads subset were used to perform Virtual screening. The integrins were submitted to Virtual screening using Sybyl-X software with the default configurations. The center of the grid was defined in the MIDAS Ca+2 ion. The size of the grid was 35Å, comprising the whole binding site. The binding site characterization showed that the region around the MIDAS ion is highly electronegative, favoring the interaction of predominantly positive ligands, but not necessarily. The output of Virtual Screening technique showed molecules with high score, which means that these molecules are good ligands to each receptor. Also, some molecules are related to another diseases, such as cancer. These results may be helpful in the design of new and potent inhibitors of integrins, mimicking other peptide ligands with increased affinity and stability.