Structures of 70 unique G protein-coupled receptors (GPCRs) have been determined, with over 370 structures in total bound to different ligands and the receptors in various conformational states. ...Structure-based drug design has been applied to an increasing number of GPCR targets over the past decade and now a few of these drug candidates have entered clinical trials. Given the length of time required for a drug to reach the market, there are no documented examples of licensed drugs being developed with the aid of a structure, but this is likely to change as current efforts come to fruition.
The promise of the intensive structural investigations of GPCRs over the past decade was that they would improve and expedite the design of drugs targeting this important therapeutic class of proteins. Tate & colleagues examine whether this strategy has paid off.
Structural insights have been revealed from X-ray co-complexes of a range of G protein-coupled receptors (GPCRs) and their allosteric ligands. The understanding of how small molecules can modulate ...the function of this important class of receptors by binding to a diverse range of pockets on and inside the proteins has had a profound impact on the structure-based drug design (SBDD) of new classes of therapeutic agents. The types of allosteric pockets and the mode of modulation as well as the advantages and disadvantages of targeting allosteric pockets (as opposed to the natural orthosteric site) are considered in the context of these new structural findings.
Allosteric binding sites are pockets that small molecules can interact with outside the orthosteric pocket used by the natural signalling molecule (agonist).
Although they were long understood to exist and be important for G protein-coupled receptors (GPCRs), the range and diversity of these allosteric pockets was not predicted, with sites buried deep inside the proteins, lodged on the side within the cell membrane, and inside the cell disrupting G protein binding.
The diversity of both the pockets themselves and how molecules modulate the function of GPCRs gives great potential for future structure-based drug design for GPCRs.
After many years of effort, recent technical breakthroughs have enabled the X‐ray crystal structures of three G‐protein‐coupled receptors (GPCRs) (β1 and β2 adrenergic and adenosine A2a) to be solved ...in addition to rhodopsin. GPCRs, like other membrane proteins, have lagged behind soluble drug targets such as kinases and proteases in the number of structures available and the level of understanding of these targets and their interaction with drugs. The availability of increasing numbers of structures of GPCRs is set to greatly increase our understanding of some of the key issues in GPCR biology. In particular, what constitutes the different receptor conformations that are involved in signalling and the molecular changes which occur upon receptor activation. How future GPCR structures might alter our views on areas such as agonist‐directed signalling and allosteric regulation as well as dimerization is discussed. Knowledge of crystal structures in complex with small molecules will enable techniques in drug discovery and design, which have previously only been applied to soluble targets, to now be used for GPCR targets. These methods include structure‐based drug design, virtual screening and fragment screening. This review considers how these methods have been used to address problems in drug discovery for kinase and protease targets and therefore how such methods are likely to impact GPCR drug discovery in the future.
This article is part of a themed section on Molecular Pharmacology of GPCR. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00695.x
Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires ...acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M
and M
receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.
Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To ...gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an α-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.
Fragment-based lead discovery Rees, David C; Congreve, Miles; Murray, Christopher W ...
Nature reviews. Drug discovery,
08/2004, Letnik:
3, Številka:
8
Journal Article
Recenzirano
Fragment-based lead discovery is gaining momentum in both large pharmaceutical companies and biotechnology laboratories as a complementary approach to traditional screening. This is because ...fragment-based approaches require significantly fewer compounds to be screened and synthesized, and are showing a high success rate in generating chemical series with lead-like properties. Compared with traditional screening hits, the starting fragments have considerably lower molecular mass, and although the binding interactions of these fragments with a target protein are weak, they are structurally understood through X-ray crystallography or NMR, and they exhibit high 'ligand efficiency'. Here, we use examples from 25 different protein targets to describe chemical strategies that exploit this structural knowledge to rapidly develop fragments into high-affinity leads.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however ...have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.
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