Enzyme inhibitor libraries

Table 3.4 continued. NON PROTEOLYTIC ENZYME INHIBITOR LIBRARIES... 

R. Wischnat, R. Martin, S. Takayama, C.-H. Wong, Che-moenzymatic Synthesis of Iminocyclitol Derivatives A Useful Library Strategy for the Development of Selective Fucosyltransfer Enzymes Inhibitors , Bioorg. Med, Chan. Lett. 1998, 8, 3353-3358. 

Dolle, R., Comprehensive survey of chemical libraries yielding enzyme inhibitors, receptor agonists and antagonists, and other biologically active agents 1992 through 1997, Mol. Diversity, 1998, 3, 199-233. 

Pirrung, M.C., Chau, J.H.-L., and Chen, J., Indexed combinatorial libraries nonoligomeric chemical diversity for the discovery of novel enzyme inhibitors, in Combinatorial Chemistry, Wilson, S.R. and Czarnik, A.W., Eds., Wiley, New York, 1997, pp. 191-206. 

Furthermore, Meldal et al. developed the idea to combine the substrate cleavage on the solid phase with an inhibitor library assay in which a substrate is synthesized and coupled to a library of putative inhibitors (34) (Fig. 10.4). The incubation of such an inhibitor library with enzymes led to cleavage and hence fluorescence in beads containing weak inhibitors. Beads containing strong inhibitors re-... 

The DOCK combinatorial docking implementation [275] was also applied for the design of novel enzyme inhibitors [276, 277]. In one of these prospective examples, Haque et al. reported potent low-nanomolar plasmepsin II aspartyl-protease inhibitors [278] from a set of several focused libraries with a best Ki value of 2 nM (cf Figure 4.5f). 

E. M., Gallop, M. A. (1995) Combinatorial organic synthesis of highly functionalized pyrrolidines identification of a potent angiotensin converting enzyme inhibitor from a mercaptoacyl proline library. J Am Chem Soc 117, 7029-7030. 

As illustrated by the examples in Table 15.30, diketopiperazines are amenable to many structural variations. These heterocycles thus seem to be well suited for the preparation of libraries for lead discovery, and have, for instance, been used for the identification of new enzyme inhibitors [368]. Libraries of diketopiperazines will, however, be sparsely diverse because the diketopiperazine ring itself is pharmacophore-rich , and will contribute significantly to the overall properties of all the members of the library (see Section 1.4). 

R Hyde-DeRuyscher, LA Paige, DJ Christensen, N Hyde-DeRuyscher, A Lim, ZL Fredericks, J Kranz, P Gallant, J Zhang, SM Rocklage, DM Fowlkes, PA Wendler, PT Hamilton. Detection of small-molecule enzyme inhibitors with peptides isolated from phage-displayed combinatorial peptide libraries. Chem Biol 7 17-25, 2000. 

Structure-based design has been effectively utilized in synthesis of inhibitors of non-proteolytic enzymes. Inhibitors of MurB, an essential bacterial enzyme required for biosynthesis of peptidoglycan, were identified using the X-ray structure of the enzyme for library design. Thiazolidinone inhibitors (8) thus identified are the first examples of small molecule inhibitors of MurB. 

Bhandari et al. (56) modified a hit structure derived from the primary screening of various libraries (>300,000 compounds) on the zinc metalloenzyme phosphomannose isomerase from the yeast Candida albicans (CaPMI) to find enzyme inhibitors as jxitential antifungal agents. During primary screening only a 1296-member SP dipeptide pool library (Lll, Fig. 9.16) showed activity on the enzyme. Its deconvolution and analytical characterization led to the discovery of a by-product, derived from incomplete coupling, that showed activity on the enzyme. This compound (9.21, Fig. 9.16) showed a weak inhibitory activity on CaPMI (ICso = 40 xM) and was selected for further chemical profiling. 

Blackburn C, Pingali A, Kehoe T, Herman LW, Wang H, Kates SA. Libraries of angiotensin converting enzyme inhibitors solid-phase synthesis and affinity selection. Bioorg. Med. Chem. Lett. 1997 7 823-826. 

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