4.5 Article

Mechanism of the irreversible inhibition of human cyclooxygenase-1 by aspirin as predicted by QM/MM calculations

Journal

JOURNAL OF MOLECULAR GRAPHICS & MODELLING
Volume 40, Issue -, Pages 99-109

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2012.12.013

Keywords

Cyclooxygenase; Aspirin; Molecular modeling; QM/MM; ONIOM; Reaction mechanism

Funding

  1. National Office of Research and Technology (Jedlik Anyos grant) [NKFP-07-A1-2008-0127]
  2. Hungarian National Infrastructure Development Program [NIIF 1057]
  3. Hungarian Academy of Sciences [MTA 11003]
  4. [TAMOP-4.2.2/B-10/1-2010-0024]

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Acetylsalicylic acid (aspirin) suppresses the generation of prostaglandin H2, which is the precursor of thromboxane A2. Aspirin acts as an acetylating agent in which its acetyl group is covalently attached to a serine residue (S530) in the active site of the cyclooxygenase-1 enzyme. The exact reaction mechanism has not been revealed by experimental methods. In this study the putative structure of human cyclooxygenase-1 was constructed from ovine cyclooxygenase-1 by homology modeling, and the acetylsalicylic acid was docked into the arachidonic acid binding cavity of the enzyme. To characterize the shape of the potential energy surface of the acetylating reaction and to determine the relative energies of the stationary points on the surface, a series of ONIOM-type quantum mechanical/molecular mechanical (QM/MM) calculations were carried out at different QM levels of theories applying electronic embedding approximations. The acetylsalicylic acid and the surrounding amino acids were included in these calculations. Frequency analyses were performed to prove the existence of first order saddle points (representing transition states) and local minima on the potential energy surface. It was found that all levels of theories predicted similar transition state geometries. The activation energy values, however, demonstrated significant dependence on the methods that were applied. All the applied dependable ab initio and DFT methods predicted that the breakage of the O gamma-H gamma and formation of the O gamma-C(acetylsalicylic acid carbonyl) bonds occur in a single elementary step. (C) 2013 Elsevier Inc. All rights reserved.

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