Current Medicinal Chemistry - Volume 19, Issue 8, 2012

Two important breakthroughs, in crystallography and in molecular simulations, moved forward investigations of the G-protein coupled receptors (GPCRs). Based on the recent crystal structures of GPCRs with agonists, and also on the results from very long simulations exceeding the microsecond frontier, it was possible to answer the fundamental questions about their multiple activation schemes in anticipation of a m Read More

G protein coupled receptors (GPCRs), also called 7TM receptors, form a huge superfamily of membrane proteins that, upon activation by extracellular agonists, pass the signal to the cell interior. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto Read More

Class A or rhodopsin-like G-protein-coupled receptors (GPCRs) constitute the largest transmembrane receptor family of the human genome. Because of their biological and pharmaceutical importance, the evolutionary history of these receptors has been widely studied. Most studies agree on the classification of the 700 members of this family into a dozen of sub-families. However, the relationship between these sub-familie Read More

Crosstalk between G protein-coupled receptors (GPCRs) is one of the key mechanisms used by the cell for integrating multiple signaling pathways. Functional crosstalk at the level of signaling pathways was initially thought to regulate receptor function. Importantly, the existence of GPCR heteromers demonstrates that direct physical interactions between GPCRs could also be behind the crosstalk phenomenon. Neurologica Read More

G protein coupled receptors (GPCRs) are a large eukaryotic protein family of transmembrane receptors that react to a signal coming from the extracellular environment to generate an intracellular response through the activation of a signal transduction pathway mediated by a heterotrimeric G protein. Their diversity, dictated by the multiplicity of stimuli to which they respond and by the variety of intracellular si Read More

G protein-coupled receptors (GPCRs) play critical roles in cellular signal transduction and are important targets for therapeutics. Although these receptors have been intensely studied for quite some time, our understanding about their mechanism of action is still incomplete. GPCR activity has traditionally been viewed within the context of two-state models where the receptor is in equilibrium between a single inactive state and Read More

The understanding of β2-adrenergic receptor (β2AR) interactions with ligands as well as the mechanism of receptor activation changed radically from 2007, when the first crystallographic structure of the receptor was reported. Since then numerous crystallographic studies described interactions with all main classes of β2AR ligands and with G proteins, which provided a great insight into the molecular structure of the Read More

The RAS/RAF/MEK signaling pathway plays a central role in mediating both proliferation and survival of cancer cells. These proteins are a group of serine/threonine kinases activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface towards both nuclear and cytosolic targets. In combination with several other signaling pathways, they can differentially alter phosphorylation sta Read More

HIV-1 integrase is one of the three viral enzymes essential to HIV replication. Consequently the development of therapeutics targeting this enzyme has been a major focus of antiretroviral research over the past two decades. Several classes of integrase inhibitors have been identified; of these the diketoacids (DKAs) show greatest promise: raltegravir (Merck & Co) has been approved by the US Food and Drug Administration (FD Read More

Adiponectin is an abundant plasma protein secreted from adipocytes. Its role in energy homeostasis is well-known, including the regulation of hydrocarbons and lipids metabolism as well as the improvement of insulin resistance. It has been thought to be a key molecule in the development of type 2 diabetes mellitus and metabolic syndrome, which are epidemiological targets for preventing cardiovascular disease. In additio Read More

Arterial hypertension is a well-known disease with a worldwide high prevalence and impaired prognosis with respect to normotensive subjects, due to increased cardiovascular mortality and morbidity. Blood pressure levels over range can be successfully controlled with adequate treatment, but more than 10% of hypertensive people have their blood pressure uncontrolled despite a therapeutic regimen of 3 or more antihyperten Read More

Testicular torsion or torsion of the spermatic cord is a surgical emergency in which misdiagnosis and inappropriate treatment can lead to male infertility. Events occurring during testicular torsion and detorsion are representative of an ischemia-reperfusion injury observed in other organs. The two most important factors determining testicular damage are the degree of twisting and the early onset of a surgical treatment to Read More

Fatty acid biosynthesis is essential for bacterial survival. In recent years, components of this biosynthetic pathway have aroused wide concern. β-Ketoacyl-acyl carrier protein synthase III (FabH) is a particularly attractive target which catalyzes the initial step of fatty acid biosynthesis. In this review, fatty acid biosynthesis, recent advances in the research of FabH as well as related inhibitors are reviewed. Finally, we also discus Read More

DNA topoisomerase I is required for DNA relaxation during a variety of cellular functions. The identification of camptothecins as specific enzyme poisons and their clinical efficacy have stimulated extensive efforts to exploit topoisomerase I as a therapeutic target for cancer. However, several limitations of camptothecins, such as low solubility and stability, high toxicity, and the occurrence of resistance, have encouraged the de Read More