Publications by authors named "Benjamin D Bax"

20 Publications

  • Page 1 of 1

Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase.

Acta Crystallogr F Struct Biol Commun 2020 Oct 15;76(Pt 10):469-476. Epub 2020 Sep 15.

Medicines Discovery Institute, School of Biosciences, Cardiff University, Cardiff CF10 3AT, United Kingdom.

Inositol monophosphatase (IMPase) is inhibited by lithium, which is the most efficacious treatment for bipolar disorder. Several therapies have been approved, or are going through clinical trials, aimed at the replacement of lithium in the treatment of bipolar disorder. One candidate small molecule is ebselen, a selenium-containing antioxidant, which has been demonstrated to produce lithium-like effects both in a murine model and in clinical trials. Here, the crystallization and the first structure of human IMPase covalently complexed with ebselen, a 1.47 Å resolution crystal structure (PDB entry 6zk0), are presented. In the complex with human IMPase, ebselen in a ring-opened conformation is covalently attached to Cys141, a residue located away from the active site. IMPase is a dimeric enzyme and in the crystal structure two adjacent dimers share four ebselen molecules, creating a tetramer with approximate 222 symmetry. In the crystal structure presented in this publication, the active site in the tetramer is still accessible, suggesting that ebselen may function as an allosteric inhibitor or may block the binding of partner proteins.
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http://dx.doi.org/10.1107/S2053230X20011310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531247PMC
October 2020

Conformational flexibility within the small domain of human serine racemase.

Acta Crystallogr F Struct Biol Commun 2020 Feb 3;76(Pt 2):65-73. Epub 2020 Feb 3.

Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, England.

Serine racemase (SR) is a pyridoxal 5'-phosphate (PLP)-containing enzyme that converts L-serine to D-serine, an endogenous co-agonist for the N-methyl-D-aspartate receptor (NMDAR) subtype of glutamate ion channels. SR regulates D-serine levels by the reversible racemization of L-serine to D-serine, as well as the catabolism of serine by α,β-elimination to produce pyruvate. The modulation of SR activity is therefore an attractive therapeutic approach to disorders associated with abnormal glutamatergic signalling since it allows an indirect modulation of NMDAR function. In the present study, a 1.89 Å resolution crystal structure of the human SR holoenzyme (including the PLP cofactor) with four subunits in the asymmetric unit is described. Comparison of this new structure with the crystal structure of human SR with malonate (PDB entry 3l6b) shows an interdomain cleft that is open in the holo structure but which disappears when the inhibitor malonate binds and is enclosed. This is owing to a shift of the small domain (residues 78-155) in human SR similar to that previously described for the rat enzyme. This domain movement is accompanied by changes within the twist of the central four-stranded β-sheet of the small domain, including changes in the φ-ψ angles of all three residues in the C-terminal β-strand (residues 149-151). In the malonate-bound structure, Ser84 (a catalytic residue) points its side chain at the malonate and is preceded by a six-residue β-strand (residues 78-83), but in the holoenzyme the β-strand is only four residues (78-81) and His82 has φ-ψ values in the α-helical region of the Ramachandran plot. These data therefore represent a crystallographic platform that enables the structure-guided design of small-molecule modulators for this important but to date undrugged target.
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http://dx.doi.org/10.1107/S2053230X20001193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010357PMC
February 2020

DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion.

J Mol Biol 2019 08 10;431(18):3427-3449. Epub 2019 Jul 10.

Dept. Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK. Electronic address:

Type II topoisomerases regulate DNA topology by making a double-stranded break in one DNA duplex, transporting another DNA segment through this break and then resealing it. Bacterial type IIA topoisomerase inhibitors, such as fluoroquinolones and novel bacterial topoisomerase inhibitors, can trap DNA cleavage complexes with double- or single-stranded cleaved DNA. To study the mode of action of such compounds, 21 crystal structures of a "gyrase" fusion truncate of Staphyloccocus aureus DNA gyrase complexed with DNA and diverse inhibitors have been published, as well as 4 structures lacking inhibitors. These structures have the DNA in various cleavage states and appear to track trajectories along the catalytic paths of the DNA cleavage/religation steps. The various conformations sampled by these multiple "gyrase" structures show rigid body movements of the catalytic GyrA WHD and GyrB TOPRIM domains across the dimer interface. Conformational changes common to all compound-bound structures suggest common mechanisms for DNA cleavage-stabilizing compounds. The structures suggest that S. aureus gyrase uses a single moving-metal ion for cleavage and that the central four base pairs need to be stretched between the two catalytic sites, in order for a scissile phosphate to attract a metal ion to the A-site to catalyze cleavage, after which it is "stored" in another coordination configuration (B-site) in the vicinity. We present a simplified model for the catalytic cycle in which capture of the transported DNA segment causes conformational changes in the ATPase domain that push the DNA gate open, resulting in stretching and cleaving the gate-DNA in two steps.
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http://dx.doi.org/10.1016/j.jmb.2019.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723622PMC
August 2019

Structure-guided design of antibacterials that allosterically inhibit DNA gyrase.

Bioorg Med Chem Lett 2019 06 22;29(11):1407-1412. Epub 2019 Mar 22.

GlaxoSmithKline, Collegeville, PA 19426, USA. Electronic address:

A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.
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http://dx.doi.org/10.1016/j.bmcl.2019.03.029DOI Listing
June 2019

A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance.

Nucleic Acids Res 2018 05;46(8):4114-4128

Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.

Imidazopyrazinones (IPYs) are a new class of compounds that target bacterial topoisomerases as a basis for their antibacterial activity. We have characterized the mechanism of these compounds through structural/mechanistic studies showing they bind and stabilize a cleavage complex between DNA gyrase and DNA ('poisoning') in an analogous fashion to fluoroquinolones, but without the requirement for the water-metal-ion bridge. Biochemical experiments and structural studies of cleavage complexes of IPYs compared with an uncleaved gyrase-DNA complex, reveal conformational transitions coupled to DNA cleavage at the DNA gate. These involve movement at the GyrA interface and tilting of the TOPRIM domains toward the scissile phosphate coupled to capture of the catalytic metal ion. Our experiments show that these structural transitions are involved generally in poisoning of gyrase by therapeutic compounds and resemble those undergone by the enzyme during its adenosine triphosphate-coupled strand-passage cycle. In addition to resistance mutations affecting residues that directly interact with the compounds, we characterized a mutant (D82N) that inhibits formation of the cleavage complex by the unpoisoned enzyme. The D82N mutant appears to act by stabilizing the binary conformation of DNA gyrase with uncleaved DNA without direct interaction with the compounds. This provides general insight into the resistance mechanisms to antibiotics targeting bacterial type II topoisomerases.
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http://dx.doi.org/10.1093/nar/gky181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934680PMC
May 2018

From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome.

ACS Med Chem Lett 2017 Oct 7;8(10):1093-1098. Epub 2017 Sep 7.

Molecular Discovery Research, Biological Sciences, and Computational Chemistry, Platform Technology & Science, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.

Selective inhibitors of phosphoinositide 3-kinase delta are of interest for the treatment of inflammatory diseases. Initial optimization of a 3-substituted indazole hit compound targeting the kinase PIM1 focused on improving selectivity over GSK3β through consideration of differences in the ATP binding pockets. Continued kinase cross-screening showed PI3Kδ activity in a series of 4,6-disubstituted indazole compounds, and subsequent structure-activity relationship exploration led to the discovery of an indole-containing lead compound as a potent PI3Kδ inhibitor with selectivity over the other PI3K isoforms.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642016PMC
October 2017

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase.

Proc Natl Acad Sci U S A 2017 05 15;114(22):E4492-E4500. Epub 2017 May 15.

Antibacterial Discovery Performance Unit, Infectious Diseases Therapy Area Unit, GlaxoSmithKline, Collegeville, PA 19426;

A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase-DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.
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http://dx.doi.org/10.1073/pnas.1700721114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465892PMC
May 2017

Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin.

Nat Commun 2015 Dec 7;6:10048. Epub 2015 Dec 7.

Antibacterial Discovery Performance Unit, Infectious Diseases, Therapy Area Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, USA.

New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a 'pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested.
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http://dx.doi.org/10.1038/ncomms10048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4686662PMC
December 2015

Crystallization and initial crystallographic analysis of covalent DNA-cleavage complexes of Staphyloccocus aureus DNA gyrase with QPT-1, moxifloxacin and etoposide.

Acta Crystallogr F Struct Biol Commun 2015 Oct 23;71(Pt 10):1242-6. Epub 2015 Sep 23.

Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.

Fluoroquinolone drugs such as moxifloxacin kill bacteria by stabilizing the normally transient double-stranded DNA breaks created by bacterial type IIA topoisomerases. Previous crystal structures of Staphylococcus aureus DNA gyrase with asymmetric DNAs have had static disorder (with the DNA duplex observed in two orientations related by the pseudo-twofold axis of the complex). Here, 20-base-pair DNA homoduplexes were used to obtain crystals of covalent DNA-cleavage complexes of S. aureus DNA gyrase. Crystals with QPT-1, moxifloxacin or etoposide diffracted to between 2.45 and 3.15 Å resolution. A G/T mismatch introduced at the ends of the DNA duplexes facilitated the crystallization of slightly asymmetric complexes of the inherently flexible DNA-cleavage complexes.
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http://dx.doi.org/10.1107/S2053230X15015290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601586PMC
October 2015

Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.

Nat Chem Biol 2015 Mar 26;11(3):189-91. Epub 2015 Jan 26.

1] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.
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http://dx.doi.org/10.1038/nchembio.1735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397581PMC
March 2015

Protein arginine deiminase 2 binds calcium in an ordered fashion: implications for inhibitor design.

ACS Chem Biol 2015 Apr 26;10(4):1043-53. Epub 2015 Jan 26.

†Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States.

Protein arginine deiminases (PADs) are calcium-dependent histone-modifying enzymes whose activity is dysregulated in inflammatory diseases and cancer. PAD2 functions as an Estrogen Receptor (ER) coactivator in breast cancer cells via the citrullination of histone tail arginine residues at ER binding sites. Although an attractive therapeutic target, the mechanisms that regulate PAD2 activity are largely unknown, especially the detailed role of how calcium facilitates enzyme activation. To gain insights into these regulatory processes, we determined the first structures of PAD2 (27 in total), and through calcium-titrations by X-ray crystallography, determined the order of binding and affinity for the six calcium ions that bind and activate this enzyme. These structures also identified several PAD2 regulatory elements, including a calcium switch that controls proper positioning of the catalytic cysteine residue, and a novel active site shielding mechanism. Additional biochemical and mass-spectrometry-based hydrogen/deuterium exchange studies support these structural findings. The identification of multiple intermediate calcium-bound structures along the PAD2 activation pathway provides critical insights that will aid the development of allosteric inhibitors targeting the PADs.
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http://dx.doi.org/10.1021/cb500933jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569063PMC
April 2015

Crystallizing Membrane Proteins in the Lipidic Mesophase. Experience with Human Prostaglandin E2 Synthase 1 and an Evolving Strategy.

Cryst Growth Des 2014 Apr 7;14(4):2034-2047. Epub 2014 Mar 7.

Membrane Structural and Functional Biology Group, School of Medicine and School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.

The lipidic mesophase or in meso method for crystallizing membrane proteins has several high profile targets to its credit and is growing in popularity. Despite its success, the method is in its infancy as far as rational crystallogenesis is concerned. Consequently, significant time, effort, and resources are still required to generate structure-grade crystals, especially with a new target type. Therefore, a need exists for crystallogenesis protocols that are effective with a broad range of membrane protein types. Recently, a strategy for crystallizing a prokaryotic α-helical membrane protein, diacylglycerol kinase (DgkA), by the in meso method was reported (Cryst. Growth. Des.2013, 14, 2846-2857). Here, we describe its application to the human α-helical microsomal prostaglandin E2 synthase 1 (mPGES1). While the DgkA strategy proved useful, significant modifications were needed to generate structure-quality crystals of this important therapeutic target. These included protein engineering, using an additive phospholipid in the hosting mesophase, performing multiple rounds of salt screening, and carrying out trials at 4 °C in the presence of a tight binding ligand. The crystallization strategy detailed here should prove useful for generating structures of other integral membrane proteins by the in meso method.
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http://dx.doi.org/10.1021/cg500157xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983278PMC
April 2014

Purification, crystallization and preliminary X-ray crystallographic studies of the Mycobacterium tuberculosis DNA gyrase ATPase domain.

Acta Crystallogr Sect F Struct Biol Cryst Commun 2013 Jun 25;69(Pt 6):679-82. Epub 2013 May 25.

Unité de Microbiologie Structurale, Institut Pasteur, CNRS UMR 3528, 25 rue du Dr Roux, 75015 Paris, France.

Mycobacterium tuberculosis DNA gyrase, a nanomachine involved in the regulation of DNA topology, is the only type II topoisomerase present in this organism and hence is the sole target of fluoroquinolones in the treatment of tuberculosis. The ATPase domain provides the energy required for catalysis by ATP hydrolysis. Two constructs corresponding to this 43 kDa domain, Mtb-GyrB47(C1) and Mtb-GyrB47(C2), have been overproduced, purified and crystallized. Diffraction data were collected from three crystal forms. The crystals belonged to space groups P1 and P21 and diffracted to resolutions of 2.9 and 3.3 Å, respectively.
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http://dx.doi.org/10.1107/S1744309113012906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668594PMC
June 2013

Integration of lead optimization with crystallography for a membrane-bound ion channel target: discovery of a new class of AMPA receptor positive allosteric modulators.

J Med Chem 2011 Jan 3;54(1):78-94. Epub 2010 Dec 3.

School of Life Sciences, University of Sussex, Brighton, United Kingdom.

A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.
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http://dx.doi.org/10.1021/jm100679eDOI Listing
January 2011

Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance.

Nat Struct Mol Biol 2010 Sep 29;17(9):1152-3. Epub 2010 Aug 29.

Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.

Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a molecular basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone antibacterial structural features.
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http://dx.doi.org/10.1038/nsmb.1892DOI Listing
September 2010

Type IIA topoisomerase inhibition by a new class of antibacterial agents.

Nature 2010 Aug 4;466(7309):935-40. Epub 2010 Aug 4.

Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.

Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class.
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http://dx.doi.org/10.1038/nature09197DOI Listing
August 2010

Discovery of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a novel clinical AMPA receptor positive modulator.

J Med Chem 2010 Aug;53(15):5801-12

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
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http://dx.doi.org/10.1021/jm1005429DOI Listing
August 2010

Challenges for and current status of research into positive modulators of AMPA receptors.

Br J Pharmacol 2010 May;160(2):181-90

Neurosciences CEDD, GlaxoSmithKline, Essex, UK.

AMPA receptors consist of a family of hetero-oligomeric (tetrameric) receptors arising from four genes, each of which encodes a distinct receptor subunit (GluA1-4). Recombinant homo-tetrameric AMPA receptors, comprising four identical subunits, are functionally active and have been used in in vitro assays. However, the many different subunit permutations make possible the functional and anatomical diversity of AMPA receptors throughout the CNS. Furthermore, AMPA receptor subunit stoichiometry influences the biophysical and functional properties of the receptor. A number of chemically diverse positive modulators of AMPA receptor have been identified which potentiate AMPA receptor-mediated activity in vitro as well as improving cognitive performance in rodents and non-human primates with several being taken further in the clinic. This review article summarizes the current status in the research on positive allosteric modulation of AMPA receptors and outlines the challenges involved in identifying a chemically distinct series of AMPA receptor positive modulators, addressing the challenges created by the heterogeneity of the AMPA receptor populations and the development of structure-activity relationships driven by homomeric, recombinant systems on high-throughput platforms. We also review the role of X-ray crystallography in the selection and prioritization of targets for lead optimization for AMPA receptor positive modulators.
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http://dx.doi.org/10.1111/j.1476-5381.2010.00726.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874841PMC
May 2010

1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3.

Bioorg Med Chem Lett 2009 Apr 28;19(8):2230-4. Epub 2009 Feb 28.

GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, Hertfordshire, UK.

A series of 1-aryl-3,4-dihydroisoquinoline inhibitors of JNK3 are described. Compounds 20 and 24 are the most potent inhibitors (pIC50 7.3 and 6.9, respectively in a radiometric filter binding assay), with 10- and 1000-fold selectivity over JNK2 and JNK1, respectively, and selectivity within the wider mitogen-activated protein kinase (MAPK) family against p38alpha and ERK2. X-ray crystallography of 16 reveals a highly unusual binding mode where an H-bond acceptor interaction with the hinge region is made by a chloro substituent.
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http://dx.doi.org/10.1016/j.bmcl.2009.02.098DOI Listing
April 2009