A5073857602- RNA and protein synthesis mechanisms
- DNA and Nucleic Acid Chemistry
- RNA modifications and cancer
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Bacteriophages and microbial interactions
- Advanced biosensing and bioanalysis techniques
- Heat shock proteins research
- Cancer therapeutics and mechanisms
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- ATP Synthase and ATPases Research
- Protein Structure and Dynamics
- Biochemical and Molecular Research
- Signaling Pathways in Disease
- Enzyme Structure and Function
- Bacterial Genetics and Biotechnology
- Cell death mechanisms and regulation
- Geology and Paleoclimatology Research
- Cancer, Hypoxia, and Metabolism
- Monoclonal and Polyclonal Antibodies Research
- Synthesis and Reactivity of Heterocycles
- Cancer-related molecular mechanisms research
- Chronic Lymphocytic Leukemia Research
- Cancer-related Molecular Pathways
Granta Design (United Kingdom)
2014-2025
TScan Therapeutics (United States)
2021-2022
Baylor Scott & White Medical Center - Temple
2021
Abcam (United States)
2017-2019
Queen Elizabeth Hospital Birmingham
2019
University of Liverpool
2004-2016
University of Leeds
1994-2004
Wayne State University
2003
University of California, Santa Cruz
1998-2003
United States Geological Survey
2002
The crystal structure of an unmodified hammerhead RNA in the absence divalent metal ions has been solved, and it was shown that this ribozyme can cleave itself when are added. This biologically active fold is same as found previously for two modified ribozymes. Addition cations at low pH makes possible to capture uncleaved metal-bound form. A conformational intermediate, having additional Mg(II) bound cleavage-site phosphate, captured by freeze-trapping prior cleavage. most significant...
The design and synthesis of novel adenosine-derived inhibitors HSP70, guided by modeling X-ray crystallographic structures these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for were highly selective over HSP90, some displayed potency against HCT116 cells. Exposure compound 12 to cells caused significant reduction cellular levels Raf-1 Her2 at concentrations similar that which cell growth arrest.
Time scale control of molecular interactions is an essential part biochemical systems, but very little known about the structural factors governing kinetics recognition. In drug design, lifetime drug-target complexes a major determinant pharmacological effects absence structure-kinetic relationships precludes rational optimization this property. Here we show that almost buried polar atoms--a common feature on protein binding sites--tend to form hydrogen bonds are shielded from water....
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is antiapoptotic member of the Bcl-2 family proteins, whose upregulation in human cancers associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report discovery our clinical candidate S64315, a selective small molecule inhibitor Mcl-1. Starting from fragment derived lead compound, have conducted structure guided optimization that led significant (3 log) improvement...
78 kDa glucose-regulated protein (Grp78) is a heat shock (HSP) involved in folding that plays role cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and isothermal titration calorimetry. The most potent compounds were 13 (VER-155008) with K(D) = 80 nM 14 60 nM. X-ray crystal structures bound ATP, ADPnP, adenosine derivative 10 revealed differences the binding site between homologous proteins.
Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as attractive target for cancer therapy. Here, we report discovery selective small molecule inhibitors Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids promising but nonselective hits were optimized using nuclear...
We describe our work to establish structure- and fragment-based drug discovery identify small molecules that inhibit the anti-apoptotic activity of proteins Mcl-1 Bcl-2. This identified hit series compounds, some which were subsequently optimized clinical candidates in trials for treating various cancers. Many protein constructs designed with suitable properties different biophysical assays structural methods. Fragment screening using ligand-observed NMR experiments several compounds each...
The dissociation rate constant kd (off-rate) is the component of ligand-protein binding with most significant potential to enhance compound potency. Here we provide theoretical and empirical data show that this parameter can be determined accurately from unpurified reaction products containing designed test compounds. This screening protocol amenable parallel chemistry, provides efficiencies time materials, complements existing methodologies for hit-to-lead phase in fragment-based drug discovery.
// Jonathan D. Moore 1,2,* , Anna Staniszewska 1,* Terence Shaw 1 Jalanie D’Alessandro Ben Davis Alan Surgenor Lisa Baker Natalia Matassova James Murray Alba Macias Paul Brough Mike Wood and Patrick C. Mahon Vernalis (R&D) Ltd, Granta Park, Cambridge, UK 2 Current address: Horizon discovery, Cambridge Research Waterbeach, * These authors contributed equally to this work Correspondence: Mahon, email: Keywords : Pyruvate dehydrogenase kinase, glycolysis, Warburg metabolism, Nov3r...
The increasing use of fragment-based lead discovery (FBLD) in industry as well academia creates a high demand for sensitive and reliable methods to detect the binding fragments act starting points drug programs. Nuclear magnetic resonance (NMR), surface plasmon (SPR), X-ray crystallography are well-established fragment finding, thermal shift fluorescence polarization (FP) assays used lesser extent. Weak affinity chromatography (WAC) was recently introduced new technology screening. study...
// Patrick Casara 1, * , James Davidson 2, Audrey Claperon 3, Gaëtane Le Toumelin-Braizat 3 Meike Vogler 4 Alain Bruno 5 Maïa Chanrion Gaëlle Lysiak-Auvity Thierry Diguarher 1 Jérôme-Benoît Starck Ijen Chen 2 Neil Whitehead Christopher Graham Natalia Matassova Pawel Dokurno Pedder Youzhen Wang 6 Shumei Qiu Anne-Marie Girard Emilie Schneider Fabienne Gravé Aurélie Studeny Ghislaine Guasconi Francesca Rocchetti Sophie Maïga 7 Jean-Michel...
Paediatric fever is a common cause of emergency department (ED) attendance. A lack prompt and definitive diagnostics makes it difficult to distinguish viral from potentially life-threatening bacterial causes, necessitating cautious approach. This may result in extended periods observation, additional radiography, the precautionary use antibiotics (ABs) prior evidence foci. study examines resource use, service costs, health outcomes.We studied an all-year prospective, comprehensive,...
The serine/threonine kinase DYRK1A has been implicated in regulation of a variety cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, differentiation, and metastasis. In addition, elevated-level activity increased severity symptoms Down's syndrome. A selective inhibitor could therefore be therapeutic benefit. We have used fragment structure-based discovery methods to identify highly selective, well-tolerated,...
We describe a novel approach for screening fragments against protein that combines the sensitivity of DNA-encoded library technology with ability to explore what will bind. Each members consists fragment which is linked photoactivatable diazirine moiety. Split and pool synthesis each set linkers version reported here containing some 70k different compounds, an individual DNA code. Incubation sample followed by photoactivation, washing subsequent PCR sequencing allows hits be identified....