Salsbury F.R.,Wake forest University |
Yuan Y.,Wake forest University |
Yuan Y.,4705 Center Blvd |
Knaggs M.H.,Wake forest University |
And 3 more authors.
Journal of Physical Chemistry B | Year: 2012
The peroxiredoxins (Prx) are ubiquitous peroxidases involved in important biological processes; however, details of their enzymatic mechanism remain elusive. To probe potential dynamics - function relationships, molecular dynamics simulations and electrostatic calculations were performed on the atypical 2-cysteine thiol peroxidase (Tpx) from Streptococcus pneumoniae and results compared to a previous study of a typical 2-cysteine Prx from Trypanosoma cruzi. The analyses indicate a commonality between both typical and atypical Prx: dynamic asymmetry. Asymmetry is observed in structure, fluctuations, and active site electrostatics. Key residues, including Glu150 and Phe153, play roles in the developing asymmetry; furthermore, in the atypical 2-Cys Tpx, Glu150 exhibits conformation fluctuations suggesting involvement in a proton shuttle. The existence of a pathway of connected residues appears to propagate the asymmetry. The commonality of asymmetry and coupling pathways in both typical and atypical Prxs suggests a driving force toward dimer asymmetry as a common feature that plays a functional role in creating one active site with a lower cysteine pKa. © 2012 American Chemical Society.
Onions S.T.,Sygnature Discovery Ltd |
Ito K.,RespiVert Ltd |
Ito K.,Imperial College London |
Charron C.E.,RespiVert Ltd |
And 19 more authors.
Journal of Medicinal Chemistry | Year: 2016
The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery. © 2016 American Chemical Society.
PubMed | RespiVert Ltd, Sygnature Discovery Ltd, Nihon University, Old Cottage Hospital and Pneumolabs UK Ltd
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2016
The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.
Slatter A.F.,CNR Institute of Population Genetics |
Campbell S.,Sygnature Discovery Ltd |
Angell R.M.,University of Sussex
Journal of Biomolecular Screening | Year: 2013
The Aurora kinases are a group of serine/threonine protein kinases that regulate key steps during mitosis, and deregulation of these proteins (e.g., by gene amplification or overexpression) has been linked to a wide variety of tumor types. Thus, Aurora-A and Aurora-B have been intensely studied as targets for anticancer therapy and are now clinically validated targets. Here we report on the development of a novel fluorescence intensity binding assay for Aurora-A kinase inhibitors using a fluorescently labeled probe compound that shows intramolecular quenching when unbound but exhibits a dramatic increase in fluorescence when bound to Aurora-A. © 2013 Society for Laboratory Automation and Screening.
Boss C.,Actelion Pharmaceuticals |
Aissaoui H.,Actelion Pharmaceuticals |
Amaral N.,Actelion Pharmaceuticals |
Bauer A.,Actelion Pharmaceuticals |
And 34 more authors.
ChemMedChem | Year: 2016
More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Gattrell W.T.,Prosidion Ltd |
Sambrook Smith C.P.,Prosidion Ltd |
Smith A.J.,Sygnature Discovery Ltd
Bioorganic and Medicinal Chemistry Letters | Year: 2012
A ligand-based approach to identify potential starting points for a dual MCH-1R antagonist/DPPIV inhibitor medicinal chemistry program was undertaken. Potential ligand pairs were identified by analysis of MCH-1R and DPPIV in vitro data. A highly targeted synthetic effort lead to the discovery of pyridone 11, a dual MCH-1R antagonist/DPPIV inhibitor with selectivity over DPP8 and DPP9. © 2011 Elsevier Ltd. All rights reserved.
Rawling M.J.,University of Nottingham |
Storr T.E.,University of Nottingham |
Bawazir W.A.,University of Nottingham |
Bawazir W.A.,King Abdulaziz University |
And 7 more authors.
Chemical Communications | Year: 2015
A heterocyclic, sp3-rich chemical scaffold was synthesised in just 6 steps via a highly regio- and diastereo-selective tandem nitrone formation/intramolecular nitrone-alkene [3+2] cycloaddition reaction. A library of 543 lead-like compounds based on the scaffold core has been produced. © The Royal Society of Chemistry 2015.