Current Topics in Medicinal Chemistry - Volume 15, Issue 24, 2015

With the apparition of concepts such as allosteric modulation and functional selectivity the field of G-protein coupled receptors drug discovery has regained its momentum. To better address this paradigm shift new screening technologies were developed. To identify novel GPCR ligands the screening method of choice was based upon functional assay for the last decade and is now being complemented by several innovative Read More

G protein-coupled receptors (GPCRs) constitute the largest group of human membrane proteins and have received significant attention in drug discovery for their important roles in physiological processes. Drug development for GPCRs has been remarkably successful and several of the most profitable pharmaceuticals on the market target members of this superfamily. Breakthroughs in structural biology for GPCRs have Read More

Binding kinetics are the rates of association and dissociation of a drug-protein complex and are important molecular descriptors for the optimization of drug binding to G-protein coupled receptors (GPCRs). There are now many examples of binding kinetics in GPCR drug discovery. In this report, the first principles and examples of binding kinetics in GPCR drug discovery are reviewed. Addressed are the influence of bin Read More

As the considerable technical challenges involved with generating crystal structures of G (guanine nucleotide- binding) protein-coupled receptors (GPCRs) are starting to be successfully addressed, opportunities to apply fragment-based drug discovery (FBDD) to this class of target are becoming a reality. GPCRs represent a large and important family of drug targets with considerable clinical and commercial interest. Wh Read More

Seven transmembrane domain receptors (7TMRs) constitute the largest family of transmembrane proteins in vertebrates and are the targets of more than 40% of currently marketed drugs. It is now accepted that these receptors are highly dynamic “microprocessors” that adopt a continuum of functionally distinct active conformations. The novel concept of biased agonism (or functional selectivity) posits that different ligands Read More

Nanobodies are therapeutic proteins derived from the variable domain (VHH) of naturally occurring heavy-chain antibodies. These VHH domains are the smallest functional fragments derived from a naturally occurring immunoglobulin. Nanobodies can be easily produced in prokaryotic or eukaryotic host organisms and their unique biophysical characteristics render these molecules ideal candidates for drug development. T Read More