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PDF File(2133KB) A Study on Binding Mo des of Nonsteroidal Anti-in ammatory Drugs to COX1 and COX2 as Obtained by Do ck4.0 a a b Eiichi AKAHO *, Chikako FUJIKAWA , Howell I. RUNION , b c Craig R. HILL and Hidehiko NAKANO a Faculty of Pharmaceutical Sciences, Kob e Gakuin University 518 Arise, Ikawadani-cho, Nishi-ku, Kob e 651-2180 JAPAN *e-mail: [email protected] b Scho ol of Pharmacy, University of the Paci c 751 Bro okside Road, Sto ckton, CA 95211 USA c Department 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-in ammatory drugs NSAIDs which selectively inhibit COX2 without a ecting an enzyme activityofCOX1would b e an ideal anti-in ammatory drug. Thus an attempt was made to examine those binding mo des of NSAIDs against COX1 and COX2 in terms of hydrogen b ond and binding energy by utilizing Do ck4.0. It was shown that binding mo de to COX2 selective NSAIDs coincided with the result rep orted in the in vitro study by R.S. Spangler Seminars in Arthritis 1996. Thus, it can be said that there is a Rheumatism, 26, 435-446 and fairly good correlation between the Do ck4.0 results and those rep orted in the in vitro study. As far as the binding mo de of COX1 selective NSAIDs is concerned one corresp onded to the in vitro study rep orted by R.S. Spangler, another did not and a third presented a medio cre conformity. It was also shown that there existed one to three H-b onds with the net total b eing at least twelve when NSAIDs such as nabumetone, meclofenamate, ni umic acid, indomethacin, sulindac, and urbiprofen were b ound to COX2. Amino acid residues involved in such hydrogen b onds 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 rep orted by R. G. Kurumbail et al. Nature, 384, 644-648 1996 but the rest of the amino acid residues were not. Keywords: Computer Do cking, Computer Drug Design, Cyclo oxygenase, COX, Nonsteroidal Anti-in ammatory Drug This pap er was presented at the 1999 Do ck user group meeting, \DOCK: Applied Structure-Based Drug Design" held on April 16-17, at the University of California at San Francisco, USA. 147 1 Intro duction With an advance of computer technology and protein science, automated do cking programs have b een develop ed and utilized in various elds[1{9]. One of the most old and well-known do cking programs is Do ck4.0[10]. The do ck program in general is designed to nd favorite orientation of a ligand in a receptor. Atypical receptor might b e an enzyme with a well-de ned active site. The ligand structure maybetaken from the crystal structure of the ligand-enzyme complex or can be drawn manually by using a chemical mo deling software. The orientation of the ligand is evaluated with a shap e scoring function and/or a function approximating ligand-enzyme binding energy. The shap e scoring function is an empirical function resembling the van der Waals attractive energy. The ligand-enzyme binding energy is taken to be approximately the sum of van der Waals attractive, van der Waals repulsive, and coulombic electrostatic energy as shown b elow[10]: lig rec X X B q q A ij i j ij + 332 E = 12 6 r r Dr ij ij ij j =1 i=1 where each term is a double sum over ligand atoms i and receptor atoms j, A and B are van ij ij der Waals repulsion and attraction parameters, r is the distance between atoms i and j, q ij i and q are the p oint charges on atoms j and j, D is the dielectric function, and 332 is a factor j that converts the electrostatic energy into kilo calories p er mole. It is said that Do ck4.0 among other do cking programs is a so-called standard program in pharmaceutical companies for general lead comp ound development[11]. However, due to its complexity in nature, diculties have b een encountered. Up on the release of Do ck4.0 in May 1997, the authors obtained it and installed it on SGIO2 : Mo del;R5000SC180MHz. Cyclo oxygenase, also known as prostaglandin endop eroxide syntheses pHs or COX, is the key enzyme of the biosynthetic pathway leading to the formation of prostaglandins. It has recently b een rep orted that this enzyme exists in two isoforms[12]. The amino acid comp ositions of the two isoforms are ab out 60 identical and their anity towards arachidonic acid, the natural substrate, app ears to b e quite similar[13]. Prostaglandins resp onsible for in ammatory pro cess can b e suciently controlled with non- steroidal anti-in ammatory drugs NSAIDs. On the other hand, NSAIDs pro duce adverse e ects on the gastrointestinal GI mucosa, kidney, and homeostasis limiting their clinical util- ity. The role of COX1 is thought to be a pro duction of \housekeeping" prostaglandin critical to auto crine / paracrine resp onses to circulating hormones, and maintenance of normal renal function, gastric mucosal integrity, and homeostasis[14]. COX2 is thought to contribute to the increase in prostaglandins observed in in ammed tissues. Therefore, anti-in ammatory drugs, which selectively inhibit COX2 without a ecting an enzyme activityofCOX1, would b e an ideal anti-in ammatory drug. Binding mo des of COX1 and COX2 to anti-in ammatory drugs must be di erent, but there are no rep orts to show the binding mo des of existing nonsteroidal anti-in ammatory drugs against COX1 and COX2. Thus an attempt was made to examine those binding mo des of NSAIDs against COX1 and COX2 by utilizing Do ck4.0. 148 2 Background in vitro studies of COX1 and COX2 using murine enzymes have b een rep orted [15, 16]. Meade et al. rep orted di erential activity of seven NSAIDs on COX1 and COX2 whichwere expressed in and isolated from Cos 1 cells. They measured IC which represented the NSAIDs concentra- 50 tion required to inhibit enzyme activityby 50. 6-MNA the active metab olite of nabumetone exhibited the lowest ratio of IC COX2/COX1 whichwas 0.1. This indicates that nabume- 50 tone is roughly 7 times more active on COX2 than on COX1. They found that sulindac and indomethacin were the least selective to COX2. Barnett et al studied di erential activity of various NSAIDs on human COX2 / COX1 ex- pressed in and puri ed from baculovirus [17]. They found that the IC ratios COX2/COX1 50 of indomethacin, anirolac, urbiprofen, ketoprofen, suprofen, naproxen, diclofenac, ibuprofen, fenclofenac, nabumetone6-MNA, meclofenamate, nimesulide, NS-398, and ni umic acid were 14.7, 12.8, 12.7, 4.6, 4.0, 3.3, 1.6, 0.6, 0.5, 0.3, 0.03, 0.02, 0.02, and 0.008 resp ectively. This study shows that indomethacin, anirolac and urbiprofen were fairly COX1 sp eci c drugs. On the other hand, nabumetone 6-MNA, meclofenamate, nimesulide, NS-398, and ni umic acid were more sp eci c inhibitors for COX2. Based on these rep orted in vitro studies on di eren- tial activity of various NSAIDs, grouping of NSAIDs in terms of COX1 / COX2 selectivity was p erformed. Indomethacin, sulindac and urbiprofen were classi ed as COX1 selective NSAIDs. Nabumetone 6-MNA, meclofenamate, and ni umic acid were classi ed as COX2 selective NSAIDs. The remaining NSAIDs, naproxen, diclofenac, and ibuprofen were termed as equip otent NSAIDs. 3 Metho dology The known structures of NAISDs were drawn by InsightI I Molecular Simulation Incorp orated and the NSAIDs were used as ligands for do cking study. COX1 and COX2 structures were ob- tained from Bro okhaven protein databank URL: http://www.p db.bnl.gov/p db-bin/p dbmain. After removing water molecules and assigning hydrogens and charges, computer do cking was p erformed. The results were evaluated according to the prop osed rule mentioned in the Back- ground section. 4 Results and Discussion Evaluation of do cking results will be p erformed based on steric complementarity. This can be called the b est tting of ligand to the enzyme pocket. There is no universal rule to judge which one exhibits the b est steric and concrete complementarity. At this p oint it is p ointed out that the following three factors are primarily involved to in uence binding conformation between a ligand and a protein. These are binding energy,hydrogen b onding, and hydrophobic- hydrophobic interaction. The binding energies of hydrogen b onds range from 1 - 7 kcal/mol while that of hydrophobic-hydrophobic interactions among methylene groups is estimated to b e 0.37 kcal/mol[18]. Therefore, the former is, on the average, ab out 10 times stronger than the latter. It is p ossible to identify the existence of hydrogen b onding quantitatively in the do cked conformation by using the chemical software InsightI I, but this program do es not quantify that of hydrophobic-hydrophobic interactions well. Taking these factors into consideration we 149 applied the following criteria to judge the relative binding selectivity of ligands to COX1 and COX2. We do not wish to establish that these are the absolute rules by which to judge the b est binding mo de of a particular ligand to a particular protein but that these criteria can be used to compare the binding selectivity of ligands to similar but di erent typ es of proteins as presented in the current study.
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