ESTUDO DA ESPECIFICIDADE DAS MMPs E SUAS INTERAÇÕES COM POTENCIAIS INIBIDORES POR MEIO DE MODELAGEM MOLECULAR

Abstract

Matrix Metalloproteinases (MMPs) are a family of enzymes, whose main function is to degrade the extracellular matrix (ECM), playing a fundamental role in several physiological and pathological processes. In recent decades, different synthetic and natural MMP inhibitors (IMMPs) have been proposed and tested in the control of several diseases involving inflammatory processes and cell progression. In this context, the main of the present work was to investigate and describe the structure and properties of the different MMPs classes from a literature research, followed by a study of the MMPs interaction with tetracycline-derivatives inhibitors applying molecular docking methodology. The literature research was qualitative and exploratory using as a source the bases the Web of Science, Scorpus, Periódicos CAPES, Scielo and published books in the area, searching for the keywords: “Matrix Metalloproteinase” and “MMP inhibitors”. The MMPs constitute a family of enzymes dependent on zinc and calcium, and 26 MMPs are currently known, classified according to the type of natural substrate and structural properties. All MMPs classes have common structural domains, being present in all of them a catalytic domain containing a Zn(II) ion and a specificity channel known as S1' pocket. To explore the specificity of MMPs, the ligands CMT-3, CMT-7, CMT-8 and Doxycycline (Dox) were docketed into the active site of MMPs representing each family: collagenases (MMP-1, MMP-13), gelatinases (MMP-2 and MMP-9), stromelysin (MMP-10), matrilysin (MMP-7) and miscellaneous MMP (MMP-13 and MMP-20, obtained from PDB , using the Autodock program. The best conformations obtained based on the Autodock binding free energy (ΔGLDBE) enabled the ranking of ligands in terms of their active site affinity. Each family of metalloenzymes, due to their structural characteristics, has different affinity for ligands. MMP-1 and MMP-13 collagenases showed greater affinity for CMT-7 with ΔGLDBE equal to -8.73 kcal.mol-1 for MMP-1 and -9.58 kcal.mol-1 for MMP-13, the gelatinase MMP-2 showed the highest affinity for CMT-8 (-10.47 kcal.mol-1 ) and MMP-9 for CMT-3 (-11.83 kcal.mol-1 ), stromelysin MMP-10 showed the highest affinity for CMT-7 (-7.86 kcal.mol-1 ), matrilysin MMP-7 showed greater affinity for CMT-8 (-8.74 kcal.mol-1 ), while MMPs without specific classification the MMP-12 and MMP-20 showed greater affinity for CMT-3 with ΔGLDBE equal to -10.58 kcal.mol-1 and -7.79 kcal.mol-1 , respectively. In general, the ligands tried to interact with the catalytic Zn(II) ion and perform H bonds and hydrophobic contacts with the side chains of the enzyme's amino acids. Complexes with greater stability are those that manage to access the enzyme's S1' specificity channel. The relative affinity of the tested ligands suggests that there is a preference for MMP-9 overall ligands. Since the most stable complex obtained in this study was MMP-9:CMT-3 (-11.83 kcal.mol-1 ) followed by MMP-12:CMT-3 (-10.58 kcal.mol-1 ), this result is in line with the literature, which states that CMT-3 is the most potent inhibitor of MMPs, being in phase II of clinical trials. The results discussed in this work represent a small contribution within a large area of study, that require much research involving different areas of knowledge for a better understanding of MMPs and their therapeutic potential, as well as in the development of the new MMPs inhibitors more selective and potent.