Utilizing Peptide Structures As Keys For Unlocking Challenging Targets

Author(s): David Fry, Hongmao Sun

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 6 , Issue 9 , 2006

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Abstract:

Three-dimensional structures of protein targets have proven to be extremely valuable for modern drug design and discovery. For cases where the structure of the protein is unattainable, such as G-protein coupled receptors (GPCRs), structural information on active ligands is still useful and helpful for deciphering the geometrical and chemical features of the active site. Peptides, constructed from easy-to-form amide backbones and featuring variable side-chains, have an inherent advantage in generating rapid quantitative structure-activity relationships (QSAR). Given the fact that peptides are natural ligands for many protein targets, structural investigation of a series of related peptides, typically carried out via nuclear magnetic resonance (NMR), can result in an accurate pharmacophore model. Such a model can be used for virtual screening, and to assist design of second-generation peptidomimetics with improved properties and design of non-peptidic leads. In this article, we will review examples in which a structural approach utilizing peptide ligands was employed to obtain a better understanding of the target active site. We will focus on cases where such information supplied guidance toward the discovery of small molecule ligands.

Keywords: Structure of peptide, NMR, pharmacophore, small molecule drug design

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Article Details

VOLUME: 6
ISSUE: 9
Year: 2006
Page: [979 - 987]
Pages: 9
DOI: 10.2174/138955706778195171
Price: $65

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