Research article summary (published 18 Oct 2009):

Matrix metalloproteinase 2 inhibition: combined quantum mechanics and molecular mechanics studies of the inhibition mechanism of (4-phenoxyphenylsulfonyl)methylthiirane and its oxirane analogue.

Full 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.

Author information

Author/s: Tao, Peng (P); Fisher, Jed F (JF); Shi, Qicun (Q); Vreven, Thom (T); Mobashery, Shahriar (S); Schlegel, H Bernhard (HB);

Affiliation: Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, USA.

Grants: CA122417 (Agency:NCI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.

Journal: Biochemistry (Biochemistry), published in United States. (Language: eng)

Reference: 2009-Oct; vol 48 (issue 41) : pp 9839-47

Dates: Created 2009/10/13; Completed 2009/11/02;

PMID: 19754151, status: MEDLINE (last retrieval date: 11/2/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Binding Sites Catalytic Domain Computer Simulation Enzyme Inhibitors - pharmacology Ethylene Oxide - pharmacology Hydroxides - chemistry; metabolism Kinetics

Kinetics Matrix Metalloproteinase 2 - antagonists & inhibitors; chemistry Models, Molecular Protein Binding Protein Conformation Sulfides - pharmacology Water - chemistry; metabolism

Associated Chemicals: Enzyme Inhibitors (0) ; Hydroxides (0) ; Sulfides (0) ; ethylene sulfide (420-12-2) ; Ethylene Oxide (75-21-8) ; Water (7732-18-5) ; Matrix Metalloproteinase 2 (EC 3.4.24.24)

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