Designability of conformation

Peptide libraries made up of millions of randomized peptide sequences have proven useful for the identification of novel ligands that may be of interest for the development of medicinally active compounds.[123,124] However, due to the short length of the individual peptides in linear peptide libraries, they possess considerable conformational flexibility and can populate multiple random-like conformations. This flexibility does not allow one to determine the precise three-dimensional orientation of the side chains, which greatly impedes structure-based design. These facts have greatly accelerated studies into conformationally restricted libraries, where constraints have been introduced to decrease peptide flexibility. However, what is really required is the design of conformationally defined and constrained templates for library display. These templates present the side chains of selected residues in a defined three-dimensional space. Thus, as an alternative to linear peptide libraries, the well-char-... 

The design of conformationally restricted H3 agonists by Shih and co-workers [20]... 

The main purpose of this section has been to highlight the rapid progress over recent years in studies of ligand-receptor interactions at a molecular level, and the new opportunities that arise for peptide mimetic design. This also emphasizes the need for new approaches and molecular tools in the design of conformationally defined, small molecule peptide and protein mimetics, which is the main topic of the remaining sections in this article. 

Molecular modelling studies led to the design of conformationally constrained diaryl ethers as well as benzopyrrohdinone derivatives [89]. This effort was extended to the synthesis of benzopyrrohdinone-based amino iso-quinohnes (32-35). Analyzing the data of these compounds, Eq. 21 was derived [72]. 

Application of CNDO/2 Calculations and X-Ray Crystallographic Analysis to the Design of Conformationally Defined Analogs of Methamphetamine... 

P. A. Bartlett, F. A. Etzkorn, T. Guo, G. Lauri, K. Liu, M. Lipton, B. P. Morgan, G. T. Shea, W. D. Shrader, and S. Waterman, in Proceedings of the Robert A. Welch Foundation Conference on Chemical Research XXXV. Chemistry at the Frontiers of Medicine, Houston, TX, Oct. 28-29, 1991, pp. 45-68 [Chem. Abstr., 118(7) 60115f]. Intuitive- and Computer-Assisted Approaches to the Design of Conformationally Restrained Peptides and Their Mimics. 

Scheme 17. The Four Types of Idealized Diene ketene Conformations. For designation of conformations, see Footnote 6 in [72e]...

This stereoelectronic approach can be used for the rational design of conformations and stability of proteins where these units are incorporated. For example, the sequence ProHypGly (Gly=glydne, fto=proline and Hyp=4(/ )-hydroxyproline) occurs approximately 300 times in collagen s triple helix. The trans configuration is required for triple helix formation, thus stabilization relative to cis should increase the folded proteins stability. The stability of the helices can be increased by incorporation of Hp (4(/ )-fluoroproline), which enforces the trans conformation. 

MMMS) 200 These techniques turned out to be a valuable tool for the design of conformational constrained analogs of biolc cally active molecules. These compounds, e.g. cyclic peptides 6.203,204) possess an artifically introduced restriction of their conformational flexibility by modifying the peptide backbone. This approach allows a more detailed investigation of the influence of the conformation on biological activity. 

Yang, R., Asatekin, A., Gleason, K.K., 2012. Design of conformal, substrate-independent surface modification for controlled protein adsorption by chemical vapor deposition (CVD). SoftMatter 8(1), 31 3. 

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