Bainbridge Island, WA, United States
Bainbridge Island, WA, United States

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Burgin A.B.,deCODE Biostructures Inc. | Magnusson O.T.,DeCODE Genetics Inc. | Singh J.,deCODE Chemistry Inc. | Witte P.,deCODE Biostructures Inc. | And 8 more authors.
Nature Biotechnology | Year: 2010

Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (Imax∼ 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit. © 2010 Nature America, Inc. All rights reserved.


Sandanayaka V.,deCODE Chemistry Inc. | Mamat B.,DeCODE Genetics Inc. | Mishra R.K.,deCODE Chemistry Inc. | Winger J.,deCODE Chemistry Inc. | And 21 more authors.
Journal of Medicinal Chemistry | Year: 2010

Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA4H) as a key target for the treatment of cardiovascular disease. We combined fragmentbased crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA4H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA4H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (Kd=26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort. © 2009 American Chemical Society.


Ameriks M.K.,Johnson and Johnson Pharmaceutical Research and Development L.L.C. | Bembenek S.D.,Johnson and Johnson Pharmaceutical Research and Development L.L.C. | Burdett M.T.,Sunesis Pharmaceuticals | Choong I.C.,Sunesis Pharmaceuticals | And 9 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A pyridazin-4-one fragment 4 (hCatS IC 50 = 170 μM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC 50 = 430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC 50 = 60 nM) and 27 (hCatS IC 50 = 40 nM). © 2010 Elsevier Ltd. All rights reserved.


Li L.,University of Chicago | Fu Q.,University of Chicago | Kors C.A.,Argonne National Laboratory | Stewart L.,deCODE Biostructures Inc. | And 3 more authors.
Microfluidics and Nanofluidics | Year: 2010

This article presents a plug-based microfluidic system to dispense nanoliter-volume plugs of lipidic cubic phase (LCP) material and subsequently merge the LCP plugs with aqueous plugs. This system was validated by crystallizing membrane proteins in lipidic mesophases, including LCP. This system allows for accurate dispensing of LCP material in nanoliter volumes, prevents inadvertent phase transitions that may occur due to dehydration by enclosing LCP in plugs, and is compatible with the traditional method of forming LCP material using a membrane protein sample, as shown by the successful crystallization of bacteriorhodopsin from Halobacterium salinarum. Conditions for the formation of LCP plugs were characterized and presented in a phase diagram. This system was also implemented using two different methods of introducing the membrane protein: (1) the traditional method of generating the LCP material using a membrane protein sample and (2) post LCP-formation incorporation (PLI), which involves making LCP material without protein, adding the membrane protein sample externally to the LCP material, and allowing the protein to diffuse into the LCP material or into other lipidic mesophases that may result from phase transitions. Crystals of bacterial photosynthetic reaction centers from Rhodobacter sphaeroides and Blastochloris viridis were obtained using PLI. The plug-based, LCP-assisted microfluidic system, combined with the PLI method for introducing membrane protein into LCP, should be useful for minimizing consumption of samples and broadening the screening of parameter space in membrane protein crystallization. © 2009 Springer-Verlag.


Roymans D.,Tibotec BVBA | De Bondt H.L.,Tibotec BVBA | Arnoult E.,Tibotec | Geluykens P.,Tibotec BVBA | And 10 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Six-helix bundle (6HB) formation is an essential step for many viruses that rely on a class I fusion protein to enter a target cell and initiate replication. Because the binding modes of small molecule inhibitors of 6HB formation are largely unknown, precisely how they disrupt 6HB formation remains unclear, and structure-based design of improved inhibitors is thus seriously hampered. Here we present the high resolution crystal structure of TMC353121, a potent inhibitor of respiratory syncytial virus (RSV), bound at a hydrophobic pocket of the 6HB formed by amino acid residues from both HR1 and HR2 heptad-repeats. Binding of TMC353121 stabilizes the interaction of HR1 and HR2 in an alternate conformation of the 6HB, in which direct binding interactions are formed between TMC353121 and both HR1 and HR2. Rather than completely preventing 6HB formation, our data indicate that TMC353121 inhibits fusion by causing a local disturbance of the natural 6HB conformation.


PubMed | deCODE Biostructures Inc.
Type: Journal Article | Journal: Nature biotechnology | Year: 2010

Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimers disease, Huntingtons disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.

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