IngentaConnect Privileged scaffolds targeting reverse-turn and helix recognition

Authors: Che, Ye¹; Marshall, Garland R¹

Source: Expert Opinion on Therapeutic Targets, Volume 12, Number 1, January 2008 , pp. 101-114(14)

Abstract:

Background: 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. Objectives: To identify `drug-like' small molecule leads capable of modulating protein-protein interactions based on common protein-recognition motifs, such as α-helices, β-strands, reverse-turns and polyproline motifs for example. Overview: 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. Conclusions: 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.

Keywords: drug discovery; helix; interaction; privileged structure; protein-protein reverse turn

Document Type: Research article

DOI: 10.1517/14728222.12.1.101

Affiliations: 1: Washington University, Center for Computational Biology and Department of Biochemistry and Molecular Biophysics, St. Louis, MO 63110, USA +1 314 362 1567; +1 314 747 3330;, Email: garland@biochem.wustl.edu

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