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Molecular Dynamics Simulations of Arachidonic Acid-Derived Pentadienyl Radical Intermediate Complexes with COX-1 and COX-2: Insights into Oxygenation Regio- and Stereoselectivity†
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posted on 2006-03-14, 00:00 authored by Kristina E. Furse, Derek A. Pratt, Claus Schneider, Alan R. Brash, Ned A. Porter, Terry P. LybrandThe two cyclooxygenase enzymes, COX-1 and COX-2, are responsible for the committed
step in prostaglandin biosynthesis and are the targets of the nonsteroidal antiinflammatory drugs aspirin
and ibuprofen and the COX-2 selective inhibitors, Celebrex, Vioxx, and Bextra. The enzymes are remarkable
in that they catalyze two dioxygenations and two cyclizations of the native substrate, arachidonic acid,
with near absolute regio- and stereoselectivity. Several theories have been advanced to explain the nature
of enzymatic control over this series of reactions, including suggestions of steric shielding and oxygen
channeling. As proposed here, selective radical trapping and spin localization in the substrate-derived
pentadienyl radical intermediate can also be envisioned. Herein we describe the results of explicit, 10 ns
molecular dynamics simulations of both COX-1 and COX-2 with the substrate-derived pentadienyl radical
intermediate bound in the active site. The enzymes' influence on the conformation of the pentadienyl
radical was investigated, along with the accessible space above and below the radical plane and the width
of several channels to the active site that could function as access routes for molecular oxygen. Additional
simulations demonstrated the extent of molecular oxygen mobility within the active site. The results suggest
that spin localization is unlikely to play a role in enzymatic control of this reaction. Instead, a combination
of oxygen channeling, steric shielding, and selective radical trapping appears to be responsible. This work
adds a dynamic perspective to the strong foundation of static structural data available for these enzymes.