title: Utilizing peptide structures as keys for unlocking challenging targets.
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.
authors.affiliation: Department of Discovery Chemistry, Hoffmann-La Roche, Nutley, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fry
authors.forename: Hongmao
authors.initials: H
authors.lastname: Sun
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation
chemical_list: D008024:Ligands; D010455:Peptides