title: Matrix metalloproteinase 2 inhibition: combined quantum mechanics and molecular mechanics studies of the inhibition mechanism of (4-phenoxyphenylsulfonyl)methylthiirane and its oxirane analogue.
abstract: The inhibition mechanism of matrix metalloproteinase 2 (MMP2) by the selective inhibitor (4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT) and its oxirane analogue is investigated computationally. The inhibition mechanism involves C-H deprotonation with concomitant opening of the three-membered heterocycle. SB-3CT was docked into the active site of MMP2, followed by molecular dynamics simulation to prepare the complex for combined quantum mechanics and molecular mechanics (QM/MM) calculations. QM/MM calculations with B3LYP/6-311+G(d,p) for the QM part and the AMBER force field for the MM part were used to examine the reaction of these two inhibitors in the active site of MMP2. The calculations show that the reaction barrier for transformation of SB-3CT is 1.6 kcal/mol lower than its oxirane analogue, and the ring-opening reaction energy of SB-3CT is 8.0 kcal/mol more exothermic than that of its oxirane analogue. Calculations also show that protonation of the ring-opened product by water is thermodynamically much more favorable for the alkoxide obtained from the oxirane than for the thiolate obtained from the thiirane. A six-step partial charge fitting procedure is introduced for the QM/MM calculations to update atomic partial charges of the quantum mechanics region and to ensure consistent electrostatic energies for reactants, transition states, and products.
authors.affiliation: Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Tao
authors.forename: Jed F
authors.initials: JF
authors.lastname: Fisher
authors.forename: Qicun
authors.initials: Q
authors.lastname: Shi
authors.forename: Thom
authors.initials: T
authors.lastname: Vreven
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: H Bernhard
authors.initials: HB
authors.lastname: Schlegel
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005027:Ethylene Oxide / Q000494:pharmacology*; D006878:Hydroxides / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013440:Sulfides / Q000494:pharmacology; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006878:Hydroxides; D061965:Matrix Metalloproteinase Inhibitors; D013440:Sulfides; D014867:Water; C013523:ethylene sulfide; D020778:Matrix Metalloproteinase 2; D005027:Ethylene Oxide