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Abstract
Matrix metalloproteinases (MMPs) play a critical role in physiological processes and pathological conditions such tumor invasion and metastasis. In recent years, a number of MMP inhibitors have been proposed, including the chemically modified tetracyclines (CMTs), which have been evaluated in preclinical cancer models showing promising results. This work provides insights into the structure and dynamics of the MMP-2 catalytic domain complexed with seven CMT (CMT-n), based on the analysis of molecular dynamics trajectories in solution. The comparative analysis of various relevant molecular aspects of the different complexes of MMP-2 and CMT-n derivatives was performed aiming to elucidate the effect of ligands on the enzyme structure. These include the radial distribution function of the water molecules around the catalytic zinc, the solvent accessible surface area for the inhibitors and the root-mean-square fluctuation for all amino acid residues. The results help to understand the differences in the binding modes of related compounds and, therefore, add to further design of novel tetracycline-based inhibitors for MMP enzymes.
Acknowledgments
B.L.M. thanks the Brazilian Agencies CAPES for a doctoral scholarship (Bolsista da Capes – Proc. n°6560-105). M.J.R. and S.F.S. thank the Fundação para a Ciência e Tecnologia (FCT), Portugal, for grants PTDC/QUI-QUI/103118/2008 and Pest-C/EQB/LA0006/2011. H.F.S. and B.L.M. thank the CNPq and FAPEMIG (Proc. No. CEX – APQ-01742-11) for support.