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Document Figure 3 The catalytic mechanism proposed by Veerapandian et al. [31] based on the x-ray structure of a difluoroketone (geminal-diol) inhibitor bound to endothiapepsin. A water molecule tightly bound to the aspartates in the native enzyme is proposed to nucleophilically attack the scissile-bond carbonyl. The resulting geminal-diol intermediate is stabilised by hydrogen bonds with the negatively charged carboxyl of aspartate 32. Fission of the scissile C-N bond is accompanied by transfer of a proton from Asp215 to the leaving amino group. B. Complementarity of the Inhibitor Page 328 Optimizing the fit of a ligand to its binding site improves the potency by burying lipophilic residues and by maximizing the number of van der Waals contacts, hydrogen bonds, and charge—charge interactions. The principles that apply to ligand binding are similar to those involved in protein folding. Inhibitor http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_328.html (1 of 2) [4/5/2004 5:25:14 PM]
Document Page 329 binding involves displacement of hydrogen-bonded water molecules from both the ligand and the binding cleft. This process is entropy favored since waters in the solvent lattice are more disordered than those bound to protein. The change in enthalpy on forming NH…CO bonds in the complex from >CO…HOH and >NH…OH 2 is favorable but relatively small [33]. The hydrophobic effect is therefore thought to play a dominant role in the energetics of binding with hydrogen bonds providing precise alignment of the ligand with respect to the catalytic apparatus. The main chain >CO and >NH groups from P 3 to P 3' of aspartic proteinase inhibitors are nearly always satisfied by hydrogen-bond interactions on formation of the complex. Therefore, given that polypeptides can form the same hydrogen bonds to the binding cleft regardless of amino acid sequence, differences in affinity for ligands of equal length must be due to other interactions at the specificity pockets, presumably those between the ligand's side chains and the enzyme. One example of optimizing these interactions for renin is the use of the cyclohexylmethyl side chain at P 1, which has been shown to improve the potency by two orders of magnitude relative to the equivalent leucine-containing inhibitor [13]. Structure/Activity Relationship (SAR) studies have shown that in many inhibitor types, the cyclohexylmethyl group is optimal for the S 1 pocket of human renin; whereas, other analogs such as cyclohexyl, cyclohexylethyl, and the very bulky dicyclohexyl and adamantyl rings generally have significantly reduced potency [10]. The use of a cyclohexylmethyl appears to introduce selectivity for renin versus other human aspartic proteinases. This has been partly rationalized for endothiapepsin where it was shown by x-ray analysis that the cyclohexylmethyl group at P 1 can force the Phe at P 3 to adopt a less energetically favorable X 2 angle. Hence, differences at the S 3 pocket in renin may allow the P 3 Phe to adopt a more favorable X 2 angle in the presence of a cyclohexyl at P 1. In contrast the S 2 site is able to accommodate a wide variety of side chains depending on inhibitor type, e.g., Phe and His are equipotent in some analogs [34]. The x-ray structures of a number of bound renin inhibitors complexed with endothiapepsin have shown that His at P 2 can adopt different X 1 angles separated by about 120 degrees [8]. In one conformation the imidazole is lying partly in the S 1' pocket, which has a definite hydrophobic character. In the other conformation, the His side chain is in a more polar environment. The ability of aspartic proteinases to accept a variety of both polar and hydrophobic groups at the P 2 position may be due to this bifurcation. Many inhibitors possess naphthylalanine side chains at P 3 and P 4 [14,24,35]. Compounds of this type are potent renin inhibitors with binding constants in the nanomolar range. Cocrystallisation of such an inhibitor with endothiapepsin revealed that one naphthalic ring is accommodated in the S 3 pocket by significant conformational changes of local enzyme side chains (Asp77 and Asp114). The other naphthalene lies in the S 4 binding region [36]. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_329.html [4/5/2004 5:25:18 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 Page 108 mulate during tre
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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Document Subsequent studies have sh
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Document Page 495 of the RNA and pr
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Document Figure 5 Some compounds wh
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Document Med Biol 1991; 306:9-21; (
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Document Page 629 ML, Clare M, Decr
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Document 236. (a) Marshall MS. TIBS
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Document site, 52, 55, 61 triad, 24
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Document Cyclotheonamide A (CtA), 2
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document [Human immunodeficiency vi
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Document antagonistic activity, 416
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Document Kininogen, 119 high molecu
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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