MODELAGEM MOLECULAR DE NOVOS INIBIDORES DAS METALOPROTEINASES DE MATRIZ (Mmps) BASEADOS EM LIGANTES Zbgs DERIVADOS DAS TETRACILINAS

Abstract

The search for new drugs to treatment of tumor diseases has driven the study of substances with recognized biological activity, such as tetracycline analogues (TCs) known as CMTs (Chemically Modified Tetracyclines). The main characteristic is that they lack the dimethylamino group at the C4 position, responsible for the antibacterial activity, potentiating

side effects such as enzymatic inhibition, more specifically, gelatinases (MMP-2 and MMP- 9), which are the component of the matrix metalloproteinase (MMPs) family. These enzymes

can degrade the extracellular matrix allowing the migration of tumor cells by the body. Among the CMTs, CMT-3 is the one with the highest affinity for the catalytic domain of gelatinases. The mechanism of inhibition of MMPs by CMT3 is partially known, but studies using theoretical methodology have shown that the increased activity of CMT-3 is due to hydrophobic interactions with the S1 'pocket of the enzyme which is the main structural difference between gelatinases and remaining MMPs. In the present study seeking to increase the interaction, specificity, and consequently the inhibitory potential of CMT-3 against MMPs, 12 substituents at the C9 position of CMT-3 based on ligands derived from aminomethylcyclines and glycyclines were proposed, then these ligands were docked inside of the MMP-9 active site. After the molecular docking simulations, the two lower energy configurations for each complex were analyzed, with configuration 1, in which the ligand does not interact directly with the catalytic zinc, was the most stable. All ligands tested had greater binding energy than unmodified CMT-3, except for glycylcline derivatives. The CMT3-A21, CMT3-A1 and CMT3-A5 analogs obtained the highest binding energy to the enzyme. However, only the MMP-9:CMT3-A21 complex has a direct interaction with the catalytic zinc and the S1’ pocket of the enzyme, doing the binding energy of this complex 2.23 Kcal.mol-1 more stable than MMP-2:CMT-3 complex. Thus, the MMP-9:CMT-3A21 complex will be the focus of subsequent studies applying Molecular Dynamics (DM) simulations to elucidate the mechanism of enzyme inhibition by identifying specific regions of the ligands interaction with the biological receptor.