Structural mimetics

The Q -heUcal turn of residues Met P5-Ala P8 exposes the last four peptide side chains for specific interactions, most of which differ from those in the pentasaccharide complex. The only structurally mimetic hydrogen bond here is from the side chain of His P6 to Tyr L32 OH, which is similar to the hydrogen bond from Rha B 4-OH in the pentasaccharide complex. An additional interaction of the peptide is another hydrogen bond of the His P6 side chain... 

Overall, these chitinase inhibitors provide an interesting example of peptide-carbohydrate mimicry. As described above for several other systems, mimicry consists of a mixture of structurally mimetic interactions and other favorable interactions with the receptor. Of the structurally mimetic interactions, the mimicry by argifin of the N-acetyl group, and part of the pyranosyl... 

In the PPA-a-AI 1 complex, a flexible loop of the enzyme, which would normally contact the substrate, is pushed outward to allow entry of the inhibitor, and one of the key aspartate residues is held in a conformation similar to that observed in the free enzyme. Therefore, some changes relative to the carbohydrate complex are required in order to accommodate the inhibitor. The structurally mimetic interactions within the catalytic site are supplemented by other specific protein-protein interactions, with a substantial buried surface area at the interface, involving 50 residues of the enzyme [171]. 

Eguchi M, McMillan M, Nguyen C, et al. (2003) Chemogenomics with peptide secondary structure mimetics. Comb. Chem. High Throughput Screen. 6 611-621. 

Saragovi, H. et al. (1992). Loops and secondary structure mimetics development and applications in basic science and rational drug discovery. Bio j Technology 10, 1131-111. 

In the late 1980s when we began the pursuit of bradykinin receptor antagonists, information of relevance to medicinal chemists was scarce. For example, not one nonpeptide antagonist of this receptor was known, nor were any series upon which to base a structure-activity relationship. Moreover, all publications described bradykinin as being highly flexible in an aqueous environment, such that no structural mimetics could be rationalized. Of course the receptors had not been cloned at that time so nothing was known about the primary sequence of the receptor or the three-dimensional structure. 

Peptides Incorporating Secondary Structure Mimetics and Inducers Houben-Weyl... 

M. Kahn, Peptide secondary structure mimetics applications to vaccines and pharmaceuticals. Farmaco 1996, 51, 87-96. 

Unfortunately, none of the analogs 34, 35, 37, or (A-unsubstituted secondary amide) 36, which would mimic a rranj -olefin geometry) showed any appreciable tubulin-polymerizing or antiproliferative activity, despite the fact that preliminary NMR studies with compound (34) in DMSO/water indicate that the preferred conformation about the 12/13 A-methyl amide bond is indeed cis, that is, the methyl group and the carbonyl oxygen are located on the same side of the partial C-N double bond (cis/trans-mtio 4/l 34 may thus be considered a direct structural mimetic of Epo D). The underlying reasons for the lack of biological activity of... 

Additionally, secondary structure mimetics can be used to introduce constraints that may either have local or global effects. The secondary structure of a peptide is dominated by energetically favoured torsion angels ( ), cp and co, together with... 

Order, structural mimetic Secondary structure mimetic Protein domain mimetic Enzyme substrate Pore former... 

Liskamp RMJ. Conformationally restricted amino acid and dipeptides, (non)peptidomimetics and secondary structure mimetics. Rec. Trav. Chim. Pays-Bas 1994 113 1-19. 

The use of fluoroarene derivatives as structural mimetics of nucleobases has been studied extensively [47, 48]. In pioneering work in this field, Kool and co-workers reported the structural similarity between natural 2 -deoxythymidine (dT) and l, 2 -dideoxy-l -(2,4-difluoro-5-methylphenyl)- 3-D-ribofuranoside 92 (dF) (see Figure 10.9) [49, 50]. 

Chemogenomics with Protein Secondary-Structure Mimetics... 

---