Matrix Metalloproteinase 2 Inhibition: Combined Quantum Mechanics and Molecular Mechanics Studies of the Inhibition Mechanism of (4-Phenoxyphenylsulfonyl)methylthiirane and Its Oxirane Analogue

摘要

The inhibition mechanism of matrix metalloproteinase 2 (MMP2) by the selective inhibitorn(4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT) and its oxirane analogue is investigated computation-nally. The inhibition mechanism involves C-H deprotonation with concomitant opening of the three-nmembered heterocycle. SB-3CT was docked into the active site of MMP2, followed by molecular dynamicsnsimulation to prepare the complex for combined quantum mechanics and molecular mechanics (QM/MM)ncalculations. QM/MMcalculations with B3LYP/6-311+G(d,p) for the QMpart and the AMBER force fieldnfor the MM part were used to examine the reaction of these two inhibitors in the active site of MMP2. Thencalculations showthat the reaction barrier for transformation of SB-3CT is 1.6 kcal/mol lower than its oxiranenanalogue, and the ring-opening reaction energy of SB-3CT is 8.0 kcal/mol more exothermic than that of itsnoxirane analogue. Calculations also show that protonation of the ring-opened product by water isnthermodynamically much more favorable for the alkoxide obtained from the oxirane than for the thiolatenobtained from the thiirane. A six-step partial charge fitting procedure is introduced for the QM/MMncalculations to update atomic partial charges of the quantum mechanics region and to ensure consistentnelectrostatic energies for reactants, transition states, and products.