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Document involves the catalytic asparates 25/25'. The structural effect of a mutation of Leu90/90' to the larger methionine is rather difficult to predict since it can either rigidify or destabilize the HIV PR dimer or it may have an effect on the catalytic efficiency of the “resistant” enzyme. Page 32 The complicated pattern of HIV resistance to protease inhibitors, in particular the appearance of compensatory mutations that alone do not confer any resistance, suggests that the key to understanding the basis of decreased susceptibility of the virus to a given drug is the kinetics of specific processing of the GAG and GAG-POL polyproteins. The reduction in sensitivity of a mutant HIV PR towards any inhibitor can be conveniently reflected by the ratio of K i mutant/K i wild type. However, this reduced inhibitor sensitivity is only one component that distinguishes mutant-form from wild-type proteases. For virus encoding of a mutant HIV PR to be viable, the mutant protease must be capable of a minimal (although not yet quantified) level of enzymatic activity towards all substrates required for maturation of the virions. This proteolytic efficiency is reflected in the specificity constants (K cat/K m) as determined for mutant and wild type HIV PRs. In order to rationalise these potentially conflicting relationships between enzymes, substrates, and inhibitors, Gulnik and his colleagues [66] introduced the term “Vitality Factor,” in which In order for the “Vitality Factor” to be predictive for the level of resistance expected for a particular drug or combination of drugs for a given resistant strain of HIV, the determination of the specificity constants (K cat/K m for mutants) must be repeated for all nine known substrates processed by HIV PR. The inhibition constants of a given compound should not depend on the substrate, but the K cat/K m ratios do and therefore vitality values will differ for different substrates. It will be expected that the mean for all nine “vitality” values will be predictive for the change in antiviral activity for a particular compound. Although those data will be derived from in vitro experiments and are clearly not without some limitations, they may help in understanding the molecular basis of resistance and may contribute some value to possible multidrug strategies for the clinical management of AIDS. III. Perspective HIV PR inhibitors with acceptable oral availability and pharmacokinetic properties offer great promise for the treatment of HIV infection and AIDS. Efficacy studies of indinavir, ritonavir, or nelfinavir using plasma viral RNA as a marker have demonstrated up to three log reductions in RNA copy numbers that are http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_32.html [4/5/2004 4:46:54 PM]
Document Page 33 sustained in many patients [67–69]. In contrast, nucleoside antiretroviral therapy that targets reverse transcriptase rarely results in more than one log reduction of viral RNA, indicating fairly poor inhibition of viral replication by this class of compounds. One of the reasons for the apparent greater in vivo antiviral activity of HIV PR inhibitors could be the mechanistic difference of the two enzymes and their respective activities in the viral life cycle. However, growing evidence of retroviral resistance to protease inhibitors remains a concern. The availability of several chemically distinct HIV PR inhibitors, including the second generation of compounds currently under preclinical development, offers a possibility of combining two or more drugs that share little cross-resistance. Also, it seems reasonable to evaluate these compounds in combination with various nucleoside and nonnucleoside reverse transcriptase inhibitors. Early clinical data from such combination therapy indicates reduction of retroviral RNA in plasma to levels lower than the currently available limit of detection [70]. This is the first indication that the application of well-chosen combination therapy can place AIDS patients in prolonged virologic and clinical remission. Undoubtedly, protein crystallography and other elements of structure-based drug design were widely applied in the discovery of HIV PR inhibitors. It will be prudent to assume that, in the absence of structural feedback, rapid discovery of several chemically different and potent inhibitors of HIV PR would have been severely impeded if not even impossible. However, structure-based drug design still remains a new and developing technology. Further success of this drug discovery technique largely depends on the development of methods of computational chemistry. Several computational approaches such as ALADDIN [71], DOCK [72], and MCDNLG [46] have been applied with a limited degree of success in a search for novel inhibitors of HIV PR and these methods will be developed further. The most difficult and challenging computational task required for full implementation of structure-based drug design involves assigning a priority to designed compounds before their synthesis, by computation of the absolute free energy of binding or by prediction of the relative difference in the binding constants of chemically related compounds. While the former approach is technically very difficult, due to the size of configurational space that must be sampled and the limited accuracy of the force field that describes atomic interactions in the molecular system [73], the latter approach has had some successes [74,75]. Nevertheless, owing to the various assumptions and approximations that underlie these techniques, such methods are useful only as order-of-magnitude estimates [74]. Further improvements of these methods heavily depend on the availability of structural and thermodynamic data for several closely related compounds that could be used to calculate parameters required for the implementation of such thermodynamic-integration cycles. The large number of high-resolution crystal structures of HIV PR http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_33.html [4/5/2004 4:46:56 PM]
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Page 51 and 52: Document 2 Structural Studies of HI
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Document receptor, it has not yet b
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Document Figure 6 Rat and human B2
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Document B. Pharmacology Figure 1 T
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Document We determined the structur
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Document Figure 3 Previously known
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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 6 Structural Implications
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Document Table 2 Naturally Occurrin
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Document All effects of the IL-1 fa
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Document 17 Structure and Functiona
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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