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Document Page 501 Because of the large number of serotypes, a successful inhibition strategy needs to consider whether it is better to have a drug that is exceedingly potent against a small subset of HRV serotypes (e.g. 30%) or a drug that is somewhat less potent but effective against most serotypes (e.g. 90%). Because of these considerations, different parameters are required to describe viral inhibition. Two important values that have been used extensively to describe potency for antipicornaviral compounds include the mean inhibitory concentration (MIC) and the MIC 80. The MIC is the concentration that inhibits the viral progeny production by 50% in a cell-based plaque assay. The mean MIC is the average MIC over the number of serotypes against which the compounds have been tested. The MIC 80 is the MIC at which at least 80% of the serotypes tested will be inhibited by at least 50%. Another way to think about the MIC 80 is that it is the MIC value for the serotype that is at the 80th percentile rank for viruses inhibited. For example, if ten viruses were tested, the MIC 80 would be the MIC concentration of the drug that inhibits the 8th most sensitive virus [15]. B. Potency and Binding Energetics It would be reasonable to assume that the activity of a drug (MIC) against a specific serotype would be related to its binding energy. This is an important consideration because algorithms that are used to predict potency rely on estimations of binding energy. The only experiment completed to directly study this correlation suggests a rough correlation in a small number of samples. This study however was limited to a small number of compounds in a single chemically similar series [78]. It is unclear whether this relationship will hold over diverse chemical entities. One could imagine a series of compounds that binds, but is ineffective at stabilizing the virion to any extent, thus ineffective in inhibiting viral replication. This appears to be what was observed when fragments of WIN compounds that only contained the A and B rings were examined. These fragments were less able to stabilize the virus to heat-induced denaturation than intact compounds. Although the binding constant for these compounds has not been determined, the diminished thermostabilization occurred at concentrations of compound sufficient to allow the compounds to be seen bound in the VP1 pocket via x-ray crystallography [79]. This observation suggests that the drug binding and inhibition have been decoupled to some degree. Another question concerning correlating binding affinity to viral inhibition is the number of sites per virion required to be occupied before the virion can no longer uncoat: all 60, or a few? Further, is there any positive or negative cooperativity in the interaction? These questions have not yet been answered. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_501.html [4/9/2004 12:37:57 AM]
Document C. Structure-Activity Relationships Page 502 Structural features, as stated above, have been found that are common to the known HRV structures. These features place constraints on compounds that have been demonstrated in a large number of structure—activity relationships. Shape considerations, hydrophobicity requirements, hydrogen-bonding requirements and compound flexibility will be discussed. Pocket-Shape Considerations Compound Length. The results of x-ray studies on several HRV serotypes have shown that the hydrophobic pockets vary in size, but all pockets impose structural constraints on compounds. The pockets, which almost completely enclose the compounds, require that both drug length and width must be limited. The results of structure—activity relationships for one series of WIN compounds have shown that the optimum length of the aliphatic linking region between the phenoxy (B ring) and isoxazole (C ring) ring is between 3 and 6 carbons (Table 2). This optimum length will vary in other series based on the extent of substitution on the A and C rings (see below) [54,80–82]. This effect on linker length is obvious both for individual serotypes like HRV14 and for the MIC 80, which measures many serotypes. This effect of pocket length can also be seen when substituents are added to either the A or C ring which would lengthen the compounds. Additions of alkyl chains of four or more carbons tend to decrease potency, whereas shorter chains may increase potency (Table 3) [54,83]. In studies on compound length, HRV14 appears to be more sensitive to longer compounds than are many other rhinoviruses. This is consistent with the observation that the hydrophobic pocket of HRV14 is longer than that of HRVs http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_502.html (1 of 2) [4/9/2004 12:38:14 AM]
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Page 591 and 592: Document Page 478 lished—was asso
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