A Study on Binding Modes of Nonsteroidal Anti-inflammatory Drugs to COX1 and COX2 as Obtained by Dock4.0

Eiichi AKAHOa*, Chikako FUJIKAWAa, Howell I. RUNIONb, Craig R. HILLb and Hidehiko NAKANOc

aFaculty of Pharmaceutical Sciences, Kobe Gakuin University,
518 Arise, Ikawadani-cho, Nishi-ku, Kobe 651-2180 JAPAN
bSchool of Pharmacy, University of the Pacific,
751 Brookside Road, Stockton, CA 95211 USA
cDepartment of Applied Chemistry, Faculty of Engineering, Himeji Institute of Technology,
2167 Shosha, Himeji, Hyogo, 671-2201 JAPAN

(Received: May 6, 1999 ; Accepted for publication: June 8, 1999 ; Published on Web: August 6, 1999)

Nonsteroidal anti-inflammatory drugs (NSAIDs) which selectively inhibit COX2 without affecting an enzyme activity of COX 1 would be an ideal anti-inflammatory drug. Thus an attempt was made to examine those binding modes of NSAIDs against COX1 and COX2 in terms of hydrogen bond and binding energy by utilizing Dock4.0. It was shown that binding mode to COX2 selective NSAIDs coincided with the result reported in the in vitro study by R.S. Spangler (Seminars in Arthritis and Rheumatism, 26, 435-446 (1996)). Thus, it can be said that there is a fairly good correlation between the Dock4.0 results and those reported in the in vitro study. As far as the binding mode of COX1 selective NSAIDs is concerned one corresponded to the in vitro study reported by R.S. Spangler, another did not and a third presented a mediocre conformity. It was also shown that there existed one to three H-bonds with the net total being at least twelve when NSAIDs such as nabumetone, meclofenamate, niflumic acid, indomethacin, sulindac, and flurbiprofen were bound to COX2. Amino acid residues involved in such hydrogen bonds were Phe A518, Arg A120, Tyr A385, His A90, Tyr A355. Met A522, Ser A353, Gln A192, Leu A352, and Arg A513. Phe A518 and His A90 were reported by R. G. Kurumbail et al. (Nature, 384, 644-648 (1996)) but the rest of the amino acid residues were not.

Keywords: Computer Docking, Computer Drug Design, Cyclooxygenase, COX, Nonsteroidal Anti-inflammatory Drug

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