By Kenneth B. Lipkowitz, Donald B. Boyd

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Extra resources for Reviews in Computational Chemistry, Volume 9

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Compound 33 was found to have a K , of 20 nM against HIV protease. Researchers at Merck96 used the X-ray crystal structure of the enzyme inhibitor complex of L-689,502 bound to HIV-1 protease97 to construct a model of Ro 31-8959 ( 2 5 ) bound to the enzyme. 98 Inspection of the minimized structure showed that the carbonyl oxygen of the P, asparagine in this inhibitor was within hydrogen-bonding distance of the NH of Asp-29 and Asp-30 in the S, binding domain of HIV-1 protease. These researchers sought a conformationally constrained cyclic ether oxygen that might be able to serve as a mimetic of this P, asparagine.

The current availability of an X-ray crystal structure of the enzyme41 has expanded the possibilities for application of such approaches. 42-44 Several examples that fall under the scope of this chapter are included in the earlier reviews and are not further described here. 45 Because earlier reviews provide extensive coverage, this chapter presents only a recent exemplary study. 48349 at the University of Pennsylvania and Merck Case Studies in Pebtide Mimetic Desim 1 1 Research Laboratories tested the in vitro performance of this mimetic by incorporating it into a known peptidic renin inhibitor of the type R-Phe-His-Ts (where Ts is a transition state analogue).

Of course, even if one is able to obtain an unbound, solution structure for the peptide, the relationship between this conformation and the structure adopted in the bound state may not be obvious. The solution structure could, for example, be completely unrelated to that found when the peptide is bound to the receptor. Conformationally rigid regions of such a solution structure clearly have the best opportunity to maintain a similar geometric arrangement when bound to a receptor. As a result of these complications, the conformation adopted by the peptide in the bound state is often less a definitive and more a working hypothesis throughout the peptide mimetic design process.

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