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Document Page 474 of the oxycarbonium ion into Neu5Ac2en, which is produced irreversibly at low levels from sialic acid by the enzyme [78]. An S N1-type mechanism has been suggested [88] that is facilitated by an activated water molecule, which can be expelled upon inhibitor binding. The catalytic mechanism could possibly proceed without an acid group: the electrostatic potential of the enzyme could lower the barrier preventing the breaking of the ketosidic bond and the solvent could protonate the aglycon after release [89]. Clearly details of the enzyme mechanism have yet to be elucidated definitively. Structural considerations indicate that only Tyr406 (and possibly Glu277) and the triarginyl cluster are essential in the enzyme mechanism and that Asp151 is implicated. B. Inhibitor Design Principles All the nearest-neighbor interactions between sialic acid or Neu5Ac2en and the protein are with totally conserved amino acids. Thus an inhibitor designed to bind only to the conserved active-site residues of neuraminidase would inhibit neuraminidase activity across all strains of influenza. This would enable the development of an antiviral drug that would affect the spread of viral replication potentially in three ways, i.e., transport through the protective mucosal layer, desialyation of freshly synthesized viral glycoproteins, and elution of progeny virions from infected cells. The development of potent inhibitors was based on the structural information of the N2 neuraminidase conserved active site and its complex with sialic acid and Neu5Ac2en [66]. There are no reports of de novo molecules designed to fit into the cavity, and the most useful approach was to consider molecules that were structurally related to Neu5Ac2en. This involved the design of molecules that would bind isosterically to Neu5Ac2en but which were modified to increase the number of favorable interaction with the protein. The method of Goodford [90] enabled the calculation of favorable binding sites for a variety of chemical probes. The validity of this method was indicated by its ability to identify the positions of the carboxylate binding site of sialic acid as an energy minima for a carboxylate probe (Figure 8a), and the successful prediction of known bound-water sites in the active sites by a water probe. Utilizing this methodology, predictions of energetically favorable substitutions to Neu5Ac2en were examined [91]. A replacement of the hydroxyl at the 4-position of the pyranose ring of Neu5Ac2en by an amino group was identified by this procedure as an energetically favorable substitution. A protonated primary amine probe identified a favorable binding site of -16 kcal mol -1 at this location and in a pocket in the active site near two conserved glutamate residues Glu119 and Glu227 (Figure 8b). This suggested that the substitution of the 4-hydroxyl group by an amino group would increase the overall binding interactions by forming a salt link with Glu119. Furthermore the substitution of the 4hydroxyl group with a much bulkier guanidinyl group would lead to even tighter binding as a result http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_474.html [4/9/2004 12:23:05 AM]
Document Figure 8 Stereo image of the residues in the active site of Tern/N9 complexed with 4-guanidino—Neu5Ac2en overlayed with GRID maps [90] (caged mesh contours) for (a) a carboxylate oxygen probe, contoured at -12 kcal/mol; (b) an amino nitrogen probe, contoured at -12 kcal/mol. of lateral interactions of the terminal nitrogens of the guanidinyl group and the carboxylate groups of Glu119 and Glu227. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_475.html (1 of 2) [4/9/2004 12:25:17 AM] Page 475
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Document 2 Structural Studies of HI
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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 Chris Tantillo. The work i
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Document Page 108 mulate during tre
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Document 4 Bradykinin Receptor Anta
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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