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For other serinyl proteases, such as Factor Xa, kallikrein and elastase, the availability of x-ray
crystallographic structure of the enzymes (apo/complexes) provides further examples in which structurebased
drug design is being advanced (Table 2). In particular, elastase-targeted drug discovery is
highlighted here as it illustrates substrate-based peptidomimetic inhibitor design strategies that have
focused on key P 2–P 3 side chain and backbone hydrogen-bonding interactions with the enzyme (for
reviews see Reference [191]). Several x-ray crystallographic structures have been determined for
pancreatic elastase [187,188,189b,190,191] and leukocyte elastase [186,187,189a], including complexes
with peptide substrate-based inhibitors having P 1 electrophilic functionalities such as benzoxazole, [188]
trifluoromethyl ketone [56,187,189], and α-,α-difluoro-β-ketoamide [190]. Recently, the design of
peptidomimetic inhibitors incorporating nonpeptidyl P 2-P 3 replacements has resulted in the discovery of
highly potent compounds [56,187]. Specifically, a lead series of highly potent trifluoromethylketonebased
inhibitors of human leukocyte elastase which incorporate a N-carboxymethyl-3-amino-6-arylpyridone
template (50, 116; see Figure 26) was developed and shown by x-ray crystallography to
provide backbone hydrogen-bonding and a novel trajectory of a P 2 group from the pyridone ring to the
enzyme. Further modification of the pyridone ring to give the bicyclic pyridopyrimidine derivative 117
was predicted from molecular modeling studies to provide additional hydrogen-bonding to the enzyme
as well as another site on the bicyclic heteroaromatic ring system for tethering various hydrophobic or
hydrophilic groups. Finally, a series of novel dipeptide-based inhibitors (e.g., trifluoromethylacetyl-Leu-
Phe-p-isoproylanilide and a peptidomimetic derivative) are particularly intriguing because they bind
“backwards” as based on analysis of the x-ray crystallography structures of their complexes with
pancreatic elastase [191]. In this binding mode the trifluoromethylacetyl moiety is proximate to the
active site Ser residue and the ligand backbone and side chain substructures make hydrogen bonding and
hydrophobic contacts with the enzyme, respectively.
Cysteinyl Proteases
The cysteinyl proteases include papain; calpains I and II; cathepsins B, H, and L; proline endopeptidase;
and interleukin-converting enzyme (ICE) and its homologs. The most well-studied cysteinyl protease is
likely papain, and the first x-ray crystallographic structures of papain [193] and a peptide
chloromethylketone inhibitor-papain complex [194] provided the first high resolution molecular maps of
the active site. Pioneering studies in the discovery of papain substrate peptide-based inhibitors having P 1
electrophilic moieties such as aldehydes [195], ketones (e.g., fluoromethylketone, which has been
determined [196] to exhibit selectivity for cysteinyl proteases versus serinyl proteases), semicarbazones,
and nitriles are noteworthy since 13C-NMR spectro-
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