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.

Do rotamer libraries reproduce the side-chain conformations of peptidic ligands from the PDB?

“…On the other hand, there are many examples of biological systems where small peptidic ligands play an important role, e.g. they can function as hormones, signal molecules and as substrates of many protein classes [23]. Therefore, predicting the 3D structure of receptorpeptide complexes, which involves the correct modeling of peptide side chains, is a relevant issue in many molecular modeling applications.…”

Pharmacophore-Based Virtual Screening

“…We demonstrated that a pharmacophore model derived from a cyclic peptide successfully identified small molecule agonists of hMC4R [63]. In this example, the pharmacophore model served as a bridge to reach small molecule space from a peptide starting point [69]. Through examination of structure-activity relationships (SAR) of three different classes of influenza endonuclease inhibitors, Parkes and coworkers proposed a 3-point minimal pharmacophore model, on the basis of which a library of a new template was designed and synthesized [70].…”

Classification of scaffold-hopping approaches

“…The development of peptides into clinically useful drugs is largely hampered by their poor metabolic stability and low bioavailability [69]. Design of small molecules to mimic the structural features of peptides using active peptide conformations as templates has shown promising results for some challenging targets [70,71]. The application has been extended to targets involved in protein-protein interactions (PPI), where small molecules are designed to mimic the interacting moieties of proteins.…”

“…Maintaining the backbone hydrogen bonding interactions is the major task for β-sheet mimetics. These strategies have been reviewed elsewhere [71], so the focus of this review will be placed on the scaffold hopping designs where derivative molecules are structurally similar to their parents.…”