Chemically modified tetracyclines as inhibitors of MMP-2 matrix metalloproteinase: a molecular and structural study.

The present study focuses on the direct interaction of chemically modified tetracyclines (CMTs) with the active site of the matrix metalloproteinase 2 (MMP-2). Molecular docking, molecular dynamics (MD) simulations, and free energy calculations were accomplished for seven CMT derivatives. New sets of parameters are proposed for structural and catalytic zinc atoms in order to study MMPs and their complexes by means of the AMBER force field. Our computational results show that six CMTs studied bind to the catalytic zinc of the MMP-2 enzyme at the O11-O12 site as proposed experimentally. The exception was the CMT-3 analogue that is found embedding within the active site, enhancing the van der Waals and hydrophobic contacts with the hydrophobic S1' pocket in the MMP-2 enzyme. The binding energy calculated in solution predicts the CMT-3 complexes as the most favorable, followed by the CMT-7 and CMT-8 analogues, respectively, which is in line with experimental findings. This work is the first step toward understanding the mechanism of CMTs as MMP inhibitors at a molecular level.