Peptidomimetic virtual

Recent examples of successful peptide-ligand based discoveries of drug-like peptidomimetics include the discovery of SST antagonists, or the discovery of non-peptidic antagonists of the recently deorphanized urotensin II receptor at Sanofi-Aventis. ° As illustrated in Fig. 3, Flohr etal. used 3D models of the NMR solution structure of cyclic peptide derivatives of Urotensin II as a template for virtual 3D pharmacophore searches which resulted into non-peptidic candidates for lead optimization. 

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

We summarize here the efforts to generate a virtual library of peptidomimetic pentameric inhibitors of the HIV PR, derived from ritonavir (Figure 4.1), developed by the Abbott Laboratories [18,19] using computer-assisted combinatorial chemistry methods [20]. 

The virtual library was then generated by attaching the selected fragments to the peptidomimetic scaffold (Figure 4.2). 

There is a free amide group, a spacer domain relating to the dialiphatic motif, and critical sulfur as found in the requisite cysteine residue of GGTase-l s substrates. Four additional GGTls included in the data set were peptidomimetics as well. Importantly, the modeling set included compounds with different (chemical scaffolds), which in theory (and as we have established in our study, in practice) should have enabled the identification of chemically diverse hits from virtual screening. 

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