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Taddese B.,University of Essex | Simpson L.M.,University of Essex | Wall I.D.,Medicines Research Center | Blaney F.E.,Memprot Consulting | Reynolds C.A.,University of Essex
Methods in Enzymology | Year: 2013

The most significant advance in modeling GPCR active states has been the β2-adrenergic receptor-Gs complex as this essentially transforms active-state modeling into homology modeling. Various different molecular dynamics-based approaches for modeling active states are presented, and a number of key applications discussed. These simulations have given insights into the activation pathway, conformational changes, dimerization, hydration, the ionic lock, ligand binding, protonation, and sodium binding. Crystallography and simulations have shown that the presence of agonist alone is unlikely to be sufficient to form the active state and that restraints applied to the G protein-binding region are required. The role of various microswitches in activation is discussed, including the controversial rotamer toggle switch. The importance of explicitly simulating experimental molecular probes to understand activation is highlighted, along with the need to ensure that such molecules are well parameterized. Approaches to loop modeling are discussed. We argue that the role of successful virtual screening against active models should not be overestimated as the main conformational changes on activation occur in the intracellular region. © 2013 Elsevier Inc.


Hill A.P.,Medicines Research Center | Redman A.M.,Moore Research | Sneddon H.F.,Medicines Research Center
Green Chemistry | Year: 2015

Further to the introduction of solvent and reagent guides at GSK, the reagent guide methodology has been adapted to score common acids and bases for use in situations where the chemistry is tolerant of a number of options. The pKa of each acid and base, and information as to whether they are generally recognised as safe are included to enhance the utility of such guides. © 2015 The Royal Society of Chemistry.


Ez-Zoubir M.,École Nationale Supérieure de Chimie de Paris | Brown J.A.,Medicines Research Center | Ratovelomanana-Vidal V.,École Nationale Supérieure de Chimie de Paris | Michelet V.,École Nationale Supérieure de Chimie de Paris
Journal of Organometallic Chemistry | Year: 2011

The efficiency of an Ir(I)/HI system has been studied. The association of hydroiodic acid with iridium has been tested in the catalytic hydroiodination of alkynes. The use of [Ir(cod)Cl]2 dimer led to clean hydroiodination reactions and afforded the corresponding vinyliodides as a mixture of derivatives, where the Markovnikov type adduct was found to be the major product (80/20 to 93/7 ratio), in good yields. The mechanism was investigated and two main pathways seemed to be involved, one based on an initial oxidative addition of HI to the Ir(I) complex and the other one based on a π-activation of the alkyne moiety. The corresponding vinyliodides were engaged in Pd-catalyzed cross-coupling (Sonogashira and Suzuki-Miyaura) reactions under organoaqueuous conditions. © 2010 Elsevier B.V. All rights reserved.


Henderson R.K.,GSK | Jimenez-Gonzalez C.,Moore Research | Constable D.J.C.,Lockheed Martin | Alston S.R.,Moore Research | And 5 more authors.
Green Chemistry | Year: 2011

Solvents make a large contribution to the environmental impact of manufacturing processes of active pharmaceutical ingredients (API), as well as playing an important role in other chemical industries, with millions of tons used and disposed of each year. GlaxoSmithKline (GSK) has previously reported on the both the development of a GSK solvent selection guide and the incorporation of solvent life cycle inventory and assessment information. The GSK solvent selection guide has been further enhanced by: • Revising the assessments of factors that impact process safety, separating reactivity from fire and explosion rankings. • More than doubling the number of solvents in the guide, to a total of 110 from the initial 47. • Adding a customised solvent selection guide appropriate for medicinal chemistry and analytical laboratories. The new GSK solvent selection guide enables GSK scientists to objectively assess solvents and determine whether existing or new solvents brought to market as 'greener' alternatives truly represent a more sustainable choice or whether they are just addressing a single issue associated with sustainability. © The Royal Society of Chemistry.


Kaur M.,University of Manchester | Reynolds S.,University of Manchester | Smyth L.J.,University of Salford | Simpson K.,Medicines Research Center | And 2 more authors.
International Immunopharmacology | Year: 2014

Background: Lymphocytes play a central role in the pathophysiology of asthma. Corticosteroids have a limited effect in severe asthma and we hypothesise that lymphocytes play a central role in corticosteroid insensitivity. We investigated the effects of corticosteroids on cytokine production from lung lymphocytes obtained from patients with moderate severe asthma (MSA) compared to mild asthma (MA) and healthy non-smokers (HNS). Methods: Bronchoalveolar lavage (BAL) cells obtained by bronchoscopy from patients with MSA and MA (n=11 and n=14 respectively) and HNS (n=7) were stimulated with CD2/3/28 beads to activate the lymphocytes, in the presence or absence of dexamethasone (0.01-1 μM). Supernatants were assayed for IL-2, IFNγ, IL-17, IL-13 and IL-10 production. Results: Dexamethasone caused variable inhibition of cytokines; 1 μM inhibited IL-10 and IL-17 by 50% or lower, while inhibition > 50% was observed for IL-2, IL-13 and IFNγ. The effect of dexamethasone on IL-13 production was reduced in MSA. Conclusion: These findings suggest that the production of specific lymphocyte derived cytokines is poorly suppressed by corticosteroids in MSA, which may be responsible for persistent airway inflammation in these patients. © 2014 Elsevier B.V. All rights reserved.


Dunford D.G.,University of Cardiff | Knight D.W.,University of Cardiff | Wheeler R.C.,Medicines Research Center
Arkivoc | Year: 2012

Copper-catalysed cyclisations of β-hydroxyhomopropargylic sulfonamides can be carried out using copper(II) acetate in hot toluene to provide generally excellent yields of the corresponding pyrroles. © ARKAT-USA, Inc.


Marshall L.J.,University of St. Andrews | Cable K.M.,Medicines Research Center | Botting N.P.,University of St. Andrews
Tetrahedron Letters | Year: 2010

The preparation of bis-protected phloroglucinol derivatives from a range of protected resorcinol substrates is presented. Functionalization was achieved via a two-step, one-pot iridium-catalyzed C-H activation/borylation/oxidation protocol. Our system gave high conversions to the arylboronic esters and good yields of the desired phenols following subsequent oxidation. A range of common protecting group categories was studied including alkyl, silyl, ether and ester. © 2010 Elsevier Ltd. All rights reserved.


Yang H.-T.,UK National Institute for Medical Research | Papoutsopoulou S.,UK National Institute for Medical Research | Belich M.,UK National Institute for Medical Research | Belich M.,Medicines Research Center | And 6 more authors.
Molecular and Cellular Biology | Year: 2012

The role of IκB kinase (IKK)-induced proteolysis of NF-κB1 p105 in innate immune signaling was investigated using macrophages from Nfkb1SSAA/SSAA mice, in which the IKK target serines on p105 are mutated to alanines. We found that the IKK/p105 signaling pathway was essential for TPL-2 kinase activation of extracellular signal-regulated kinase (ERK) mitogen-activate protein (MAP) kinase and modulated the activation of NF-κB. The Nfkb1SSAA mutation prevented the agonist-induced release of TPL-2 from its inhibitor p105, which blocked activation of ERK by lipopolysaccharide (LPS), tumor necrosis factor (TNF), CpG, tripalmitoyl-Cys-Ser-Lys (Pam3CSK), poly(I · C), flagellin, and R848. The Nfkb1SSAA mutation also prevented LPS-induced processing of p105 to p50 and reduced p50 levels, in addition to decreasing the nuclear translocation of RelA and cRel. Reduced p50 in Nfkb1SSAA/SSAA macrophages significantly decreased LPS induction of the IκBξ-regulated Il6 and Csf2 genes. LPS upregulation of Il12a and Il12b mRNAs was also impaired although specific blockade of TPL-2 signaling increased expression of these genes at late time points. Activation of TPL-2/ERK signaling by IKK-induced p105 proteolysis, therefore, induced a negative feedback loop to downregulate NF-κB-dependent expression of the proinflammatory cytokine interleukin-12 (IL-12). Unexpectedly, TPL-2 promoted soluble TNF production independently of IKK-induced p105 phosphorylation and its ability to activate ERK, which has important implications for the development of anti-inflammatory drugs targeting TPL-2. © 2012, American Society for Microbiology.


Molloy J.J.,University of Strathclyde | Law R.P.,University of Strathclyde | Law R.P.,Medicines Research Center | Fyfe J.W.B.,University of Strathclyde | And 3 more authors.
Organic and Biomolecular Chemistry | Year: 2015

A modular synthesis of functionalised biaryl phenols from two boronic acid derivatives has been developed via one-pot Suzuki-Miyaura cross-coupling, chemoselective control of boron solution speciation to generate a reactive boronic ester in situ, and oxidation. The utility of this method has been further demonstrated by application in the synthesis of drug molecules and components of organic electronics, as well as within iterative cross-coupling. © The Royal Society of Chemistry 2015.


Poingdestre S.-J.,University of Oxford | Goodacre J.D.,Medicines Research Center | Weller A.S.,University of Oxford | Willis M.C.,University of Oxford
Chemical Communications | Year: 2012

The use of the electron-rich diphosphine ligand, dcpe, allows the efficient and highly linear selective hydroacylative coupling of aldehydes, including aryl examples, with a range of alkynes. © 2012 The Royal Society of Chemistry.

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