Privileged scaffolds targeting reverse-turn and helix recognition.

Washington University, Center for Computational Biology and Department of Biochemistry and Molecular Biophysics, St. Louis, MO 63110, USA.
Expert Opinion on Therapeutic Targets (Impact Factor: 4.9). 02/2008; 12(1):101-14. DOI: 10.1517/14728222.12.1.101
Source: PubMed

ABSTRACT Protein-protein interactions dominate molecular recognition in biologic systems. One major challenge for drug discovery arises from the very large surfaces that are characteristic of many protein-protein interactions.
To identify 'drug-like' small molecule leads capable of modulating protein-protein interactions based on common protein-recognition motifs, such as alpha-helices, beta-strands, reverse-turns and polyproline motifs for example.
Many proteins/peptides are unstructured under physiologic conditions and only fold into ordered structures on binding to their cellular targets. Therefore, preorganization of an inhibitor into its protein-bound conformation reduces the entropy of binding and enhances the relative affinity of the inhibitor. Accordingly, this review describes a general strategy to address the challenge based on the 'privileged structure hypothesis' [Che, PhD thesis, Washington University, 2003] that chemical templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as small-molecule inhibitors of protein-protein interactions. The authors highlight recent advances in the design of privileged scaffolds targeting reverse-turn and helical recognition.
Privileged scaffolds targeting common protein-recognition motifs are useful to help elucidate the receptor-bound conformation and to provide non-peptidic, bioavailable substructures suitable for optimization to modulate protein-protein interactions.


Available from: Ye Che, Jan 02, 2015
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