netLibrary - eBook Summary Structure-based Drug Design by ...

Document
Page 595
the MC1 receptor and the Arg side chain of the peptide ligand. The primary contact residues of this
particular MC1 receptor model were all transmembrane domain derived and lie within 4–7.5 angstrom
(centroid to centroid). In conclusion, the development and refinement of 3D structural models of GPCR
targets, iterative site-directed mutagenesis studies, and systematic testing of key agonists and/or
antagonists will undoubtedly make a significant impact in the structure-based drug design of
peptidomimetic and nonpeptide ligands at these receptors. Such work may be expected to synergize well
with ligand-based pharmacophore modeling strategies which have become quite sophisticated in recent
years as the results of advanced computational chemistry methodologies.
B. Protease Targets
Protease-inhibitor drug discovery illustrates significant success in both mechanistic and 3D structurebased
drug discovery for each of the representative classes (i.e., aspartyl, serinyl, metallo, and cysteinyl)
as exemplified in Table 2 (for a review see Reference 142a). In retrospect, pioneering achievements in
the design of peptidomimetic inhibitors of angiotensin-converting enzyme (for reviews see References
142b,142c) to have led to 45 (Captopril [51]) and 46 (Enalapril [52]). Such work has provided great
impetus to the area of proteasetargeted drug discovery. Over the past two decades a pervasive effort
integrating substrate-based inhibitor design, x-ray crystallography or NMR spectroscopy of inhibitorprotease
complexes, high-throughput mass screening, and combinatorial chemical technologies has
evolved to further advance this area of research.
Aspartyl Proteases
The aspartyl proteases include pepsin, renin, cathepsin-D, chymosin, and gastricsin as well as microbial
enzymes (e.g., penicillopepsin, rhizopuspepsin, and endothiapepsin) and retroviral proteases (e.g., HIV-
1 protease). The first high-resolution x-ray crystallographic structures of this protease family were
determined for penicillopepsin [143], rhizopuspepsin [144], endothiapepsin [145], pepsinogen [146],
and pepsin [147]. Based on homology-building strategies, 3D structural models of renin were
subsequently constructed [148] to first guide the structure-based design of peptidomimetic inhibitors (for
a review see Reference 149). Furthermore, in several cases the x-ray crystallographic structures of renin
inhibitors were determined [150] as ligand-enzyme complexes with rhizopuspepsin, endothiapepsin, or
pepsin. Eventually, the x-ray crystallographic structures of renin (apo/complexes) were achieved to
provide high-resolution molecular maps of the target enzyme [151]. As illustrated in Figure 22, substratebased
inhibitors such as the highly potent peptidomimetic 95 [151a] show well-defined hydrophobic
pockets for the P 3-P 1' side chains as well
http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_595.html [4/9/2004 1:20:17 AM]