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Document Figure 5 (Continued) Page 224 versus IC 50=15 nM for cAPK). Yet enhancement of specificity utilizing the inhibitor CGP52411 (Figure 4), whose selectivity originates in the occupancy by one of the anilino moieties of the inhibitor in the region of the enzyme cleft that normally binds the ribose ring of ATP, is considerable. The inhibitor CGP52411 inhibits the EGFR tyrosine kinase with an IC 50 value of 300 nM while it is less active by at least two orders of magnitude on a panel of protein kinases including cAPK, phosphorylase kinase, casein kinase, protein kinase C (most isoforms), and v-abl, c-lyn, c-fgr tyrosine kinases. Hence, the three-dimensional model of EGFR tyrosine kinase rationalizes the specificity of the CGP52411 inhibitor. This model suggests that analysis of the putative regions of the ribose binding of ATP in other kinases through template modeling would provide the required chemical modification of pharmacophores to enhance their selectivity. In modeling, the use of the bidendate hydrogen bonding provided by the linker region (Figure 3a) of the conserved http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_224.html [4/5/2004 5:07:34 PM]
Document protein kinase core is essential. Yet to predict the region of the structure of the inhibitor that will form these strong Watson-Crick hydrogen bonds remains difficult. Page 225 The use of the 6-amino group and N1 nitrogen of the purine base to model the pharmacophore, as seen with staurosporine, is not possible in two other adenine-type inhibitors. Both isopentenyl adenine, a nonspecific inhibitor of protein kinases, and olomoucin, a more specific inhibitor of Ser/Thr protein kinases, are modified only at the 6-amino group position. Thus, bidentate hydrogen-bond formation as seen in the ATP purine base is not possible. Furthermore, there are inhibitors that do not contain the chemical structure of adenine, for example des-chloro-flavopyridol, a potent inhibitor of cdc-2 cell cycle kinase. In crystallographic analysis of the binding of three inhibitors, olomoucin (OLO), isopentenyl adenine (ISO) and des-chloro-flavopyridol (DFP) to inactive CDK-2 cell cycle protein kinase, Kim and coworkers [26] have provided additional insight into the binding of adenine-and nonadenine-based inhibitors. Inhibitors with purine rings (OLO and ISO) bind in relatively the same area of the binding cleft as the adenine ring of ATP. Relative orientation of each purine ring with respect to the protein is different for all three ligands. This is most likely due to the fact that the 6-amino group of adenine in ATP is replaced by an isopentenylamino group in ISO and by the bulky benzylamino group in OLO. In the case of the third inhibitor, which is not an adenine derivative, the benzopyran ring occupies approximately the same region as the purine ring of ATP. The two ring systems overlap in the same plane but benzopyran is rotated about 60 degrees relative to the adenine of ATP. In this orientation, two strong bidendate hydrogen bond are formed with the oxygens in the 4th and 5th positions of the inhibitor. Furthermore, these bonds are the same ones formed by the 6-amino group and N1 nitrogen of the adenine ring. Crystallographic analysis has shown that both the substrate and ATP-binding clefts are structurally conserved yet differ in the surface charges between individual protein kinases. The structural template of the protein kinase family as discovered in the structure solution of cAPK predicts these differences. Template modeling provides a rational basis for the design of specific inhibitors for protein kinases based on the ATP binding site [25]. This is the first significant step in the design of specific inhibitors targeted at the ATP site. Recent work has now shown the conformational diversity of inhibitors binding in the interdomain ATPbinding cleft [26]. Although the residues of the protein kinase catalytic core that form the bidentate donor-acceptor bond with inhibitors are identical throughout different structures, the residues of the inhibitors vary greatly. All inhibitors use this common bidentate bond yet the specificity lies in several other bonds formed between the inhibitor and specific regions of the individual protein kinases. Furthermore, it is difficult to model http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_225.html [4/5/2004 5:07:35 PM]
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Structure-based Drug Design 14 Stru
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Document 2 Structural Studies of HI
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Document dine (3TC), and 2',3'-dide
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Document Analysis of various HIV-1
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Document Table 3 HIV-1 RT Amino Aci
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Document ever, once an NNRTI is bou
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Document Chris Tantillo. The work i
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Document 106. Cirino NM, Cameron CE
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Document dine) and didanosine (dide
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Document Page 108 mulate during tre
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Document when metals are bound. Fin
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Document 4 Bradykinin Receptor Anta
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Document receptor, it has not yet b
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Document We determined the structur
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Document large solvent channels and
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Document Table 1 Inhibition Data fo
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Document Page 166 As predicated, th
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Document References 1. Parks RE Jr.
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Document 17. Ealick SE, Rule SA, Ca
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Page 257 and 258: Document 29. Baker ME. Genealogy of
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Document Table 1 Approval Indicatio
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Document Page 488 against most of t
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Document A. The Canyon Page 491 The
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Document Figure 5 Some compounds wh
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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