scholarly journals Structure of avian influenza hemagglutinin in complex with a small molecule entry inhibitor

2020 ◽  
Vol 3 (8) ◽  
pp. e202000724
Author(s):  
Aleksandar Antanasijevic ◽  
Matthew A Durst ◽  
Han Cheng ◽  
Irina N Gaisina ◽  
Jasmine T Perez ◽  
...  
Keyword(s):  
Small Molecule ◽  
Specific Activity ◽  
Influenza Infection ◽  
Critical Role ◽  
Fusion Peptide ◽  
Nmr Studies ◽  
X Ray ◽  
X Ray Crystallography ◽  
Influenza Hemagglutinin ◽  
Group 1

HA plays a critical role in influenza infection and, thus HA is a potential target for antivirals. Recently, our laboratories have described a novel fusion inhibitor, termed CBS1117, with EC50 ∼3 μM against group 1 HA. In this work, we characterize the binding properties of CBS1117 to avian H5 HA by x-ray crystallography, NMR, and mutagenesis. The x-ray structure of the complex shows that the compound binds near the HA fusion peptide, a region that plays a critical role in HA-mediated fusion. NMR studies demonstrate binding of CBS1117 to H5 HA in solution and show extensive hydrophobic contacts between the compound and HA surface. Mutagenesis studies further support the location of the compound binding site proximal to the HA fusion peptide and identify additional amino acids that are important to compound binding. Together, this work gives new insights into the CBS1117 mechanism of action and can be exploited to further optimize this compound and better understand the group specific activity of small-molecule inhibitors of HA-mediated entry.

Solution multinuclear (31P,111Cd,77Se) magnetic resonance studies of cadmium complexes of heterocyclic aromatic thiones and the structure of [tetrakis(2(1H)-pyridinethione)cadmium] nitrate, [Cd(C5H5NS)4](NO3)2

2000 ◽  
Vol 78 (5) ◽  
pp. 590-597 ◽  
Author(s):  
Umarani Rajalingam ◽  
Philip AW Dean ◽  
Hilary A Jenkins
Keyword(s):  
Cadmium Nitrate ◽  
Cadmium Complexes ◽  
Nmr Studies ◽  
X Ray ◽  
X Ray Crystallography ◽  
Stoichiometric Reaction ◽  
Complex Salts ◽  
Reduced Temperature ◽  
Aromatic Heterocyclic ◽  
Phosphine Chalcogenides

The complex salts CdL4(O3SCF3)2 (L = 2(1H)-pyridinethione (Py2SH), 4(1H)-pyridinethione (Py4SH), or 2(1H)-quinolinethione (Q2SH)) have been synthesized by the stoichiometric reaction of Cd(O3SCF3)2 and the appropriate thione. Both ambient-temperature 13C and reduced-temperature 111Cd NMR of CdL4(O3SCF3)2 in solution are consistent with L being bound through sulfur. Reduced-temperature NMR (31P, 77Se, 111Cd, as appropriate) of mixtures of CdL4(O3SCF3)2 and Cd(EPCy3)4(O3SCF3)2 (E = Se, Cy = c-C6H11) and of Cd(EPCy3)4(O3SCF3)2 (E = S, Se) and L in solution provides evidence for various [CdLn(EPCy3)4-n]2+. Similarly, reduced-temperature metal NMR of [CdL4]2+ and [CdL'4]2+ (L, L' = Py2SH, Py4SH, Q2SH; L not equal L') in solution shows the formation of [CdLnL'4-n]2+. Thus it has been demonstrated that at reduced temperature [CdL4]2+ is intact in solution and exchange of L is slow on the timescale of the metal chemical shift differences. From the NMR studies of Cd(EPCy3)4(O3SCF3)2 (E = S, Se):L mixtures, the binding preferences are found to be L > EPCy3 in solution. Similarly, from the reduced temperature metal NMR spectra of mixtures where L and L' compete for Cd(II) in solution, the binding preferences are Py4SH > Py2SH > Q2SH. The structure of Cd(Py2SH)4(NO3)2 (4) has been determined by single crystal X-ray analysis. Colorless crystals of 4 are tetragonal, I4(1)/acd with 8 molecules per unit cell of dimensions a = 18.660(3), c = 15.215(3) Å. The structure is comprised of recognizable NO3- anions and [Cd(Py2SH)4]2+ cations. In the cations, which have S4 symmetry, the ligands are S-bound. A network of NH···O hydrogen bonds links the cations and anions.Key words: aromatic heterocyclic thiones, cadmium complexes, phosphine chalcogenides, 111Cd, 31P, 77Se NMR, X-ray crystallography.

scholarly journals Silylated gallium and indium chalcogenide ring systems as potential precursors to ME (E=O, S) materials

2013 ◽  
Vol 11 (7) ◽  
pp. 1225-1238
Author(s):  
Iliana Medina-Ramírez ◽  
Cynthia Floyd ◽  
Joel Mague ◽  
Mark Fink
Keyword(s):  
Thermal Decomposition ◽  
Room Temperature ◽  
Membered Ring ◽  
Molecular Structures ◽  
Nmr Studies ◽  
X Ray ◽  
X Ray Crystallography ◽  
High Yields ◽  
Vt Nmr ◽  
State 1

AbstractThe reaction of R3M (M=Ga, In) with HESiR′3 (E=O, S; R′3=Ph3, iPr3, Et3, tBuMe2) leads to the formation of (Me2GaOSiPh3)2(1); (Me2GaOSitBuMe2)2(2); (Me2GaOSiEt3)2(3); (Me2InOSiPh3)2(4); (Me2InOSitBuMe2)2(5); (Me2InOSiEt3)2(6); (Me2GaSSiPh3)2(7); (Et2GaSSiPh3)2(8); (Me2GaSSiiPr3)2(9); (Et2GaSSiiPr3)2(10); (Me2InSSiPh3)3(11); (Me2InSSiiPr3)n(12), in high yields at room temperature. The compounds have been characterized by multinuclear NMR and in most cases by X-ray crystallography. The molecular structures of (1), (4), (7) and (8) have been determined. Compounds (3), (6) and (10) are liquids at room temperature. In the solid state, (1), (4), (7) and (9) are dimers with central core of the dimer being composed of a M2E2 four-membered ring. VT-NMR studies of (7) show facile redistribution between four- and six-membered rings in solution. The thermal decomposition of (1)–(12) was examined by TGA and range from 200 to 350°C. Bulk pyrolysis of (1) and (2) led to the formation of Ga2O3; (4) and (5) In metal; (7)–(10) GaS and (11)–(12) InS powders, respectively.

scholarly journals Identification of a pH sensor in Influenza hemagglutinin using X-ray crystallography

2020 ◽  
Vol 209 (1) ◽  
pp. 107412 ◽  
Author(s):  
Aleksandar Antanasijevic ◽  
Matthew A. Durst ◽  
Arnon Lavie ◽  
Michael Caffrey
Keyword(s):  
Ph Sensor ◽  
X Ray ◽  
X Ray Crystallography ◽  
Influenza Hemagglutinin

scholarly journals Supersize Cp! Tetrabenzo[a,c,g,i]fluorenyl complexes of yttrium

2017 ◽  
Vol 95 (4) ◽  
pp. 363-370 ◽  
Author(s):  
Jianlong Sun ◽  
David J. Berg ◽  
Brendan Twamley
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Magnetic Resonance ◽  
Ethylene Polymerization ◽  
Nmr Studies ◽  
X Ray ◽  
X Ray Crystallography ◽  
Trinuclear Cluster ◽  
Polymerization Catalyst ◽  
Dynamic Nuclear Magnetic Resonance ◽  
Trimethylsilyl Isocyanate

The synthesis of tetrabenzo[a,c,g,i]fluorenyl (Tbf) yttrium dialkyl complexes, (Tbf)Y(CH2SiMe3)2(L) (L = tetrahydrofuran (THF), 1; L = bipy, 2), by direct protonolysis of the tris(alkyl) complex, Y(CH2SiMe3)3(THF)2, are reported. The X-ray crystal structures of 1 and 2 display the helical twisting typically observed for the Tbf ligand. Dynamic nuclear magnetic resonance (NMR) studies on 1 show a barrier to Tbf helical inversion (epimerization or “wagging”) of 38.1 ± 0.5 kJ mol−1. The reaction of 1 with acidic hydrocarbons such as 1,3-bis(trimethylsilyl)cyclopentadiene or trimethylsilylacetylene results in protonolysis to form the mixed Cp derivative [(Tbf){C5H3(SiMe3)2}Y(CH2SiMe3)(THF)] (3) or [(Tbf)Y(CCSiMe3)2(THF)]n (4), respectively. In the case of 4, a small amount of the trinuclear cluster (Tbf)Y3(μ3-CCSiMe3)2(μ2-CCSiMe3)3(CCSiMe3)3(THF)2 (5) was isolated and characterized by X-ray crystallography. Dialkyl 1 undergoes smooth insertion of trimethylsilyl isocyanate to afford [(Tbf)Y{κ2-(N,O)-Me3SiN(Me3SiCH2)CO}2(THF)] (6) but it does not react with alkenes. Treating 1 with [Ph3C]+[B(C6F5)4]− in bromobenzene generates a moderately active ethylene polymerization catalyst (36 kg mol−1 h−1 bar−1).

scholarly journals The critical role of QM/MM X-ray refinement and accurate tautomer/protomer determination in structure-based drug design

2020 ◽  
Author(s):  
Oleg Y. Borbulevych ◽  
Roger I. Martin ◽  
Lance M. Westerhoff
Keyword(s):  
Drug Design ◽  
Critical Role ◽  
Pharmaceutical Research ◽  
Energy Functional ◽  
Structural Refinement ◽  
Structure Based Drug Design ◽  
X Ray ◽  
X Ray Crystallography ◽  
Refinement Method ◽  
The Impact

Abstract Conventional protein:ligand crystallographic refinement uses stereochemistry restraints coupled with a rudimentary energy functional to ensure the correct geometry of the model of the macromolecule—along with any bound ligand(s)—within the context of the experimental, X-ray density. These methods generally lack explicit terms for electrostatics, polarization, dispersion, hydrogen bonds, and other key interactions, and instead they use pre-determined parameters (e.g. bond lengths, angles, and torsions) to drive structural refinement. In order to address this deficiency and obtain a more complete and ultimately more accurate structure, we have developed an automated approach for macromolecular refinement based on a two layer, QM/MM (ONIOM) scheme as implemented within our DivCon Discovery Suite and "plugged in" to two mainstream crystallographic packages: PHENIX and BUSTER. This implementation is able to use one or more region layer(s), which is(are) characterized using linear-scaling, semi-empirical quantum mechanics, followed by a system layer which includes the balance of the model and which is described using a molecular mechanics functional. In this work, we applied our Phenix/DivCon refinement method—coupled with our XModeScore method for experimental tautomer/protomer state determination—to the characterization of structure sets relevant to structure-based drug design (SBDD). We then use these newly refined structures to show the impact of QM/MM X-ray refined structure on our understanding of function by exploring the influence of these improved structures on protein:ligand binding affinity prediction (and we likewise show how we use post-refinement scoring outliers to inform subsequent X-ray crystallographic efforts). Through this endeavor, we demonstrate a computational chemistry ↔ structural biology (X-ray crystallography) "feedback loop" which has utility in industrial and academic pharmaceutical research as well as other allied fields.

scholarly journals Multiple binding modes of a small molecule to human Keap1 revealed by X-ray crystallography and molecular dynamics simulation

FEBS Open Bio ◽  
2015 ◽  
Vol 5 (1) ◽  
pp. 557-570 ◽  
Author(s):  
Mikiya Satoh ◽  
Hajime Saburi ◽  
Tomoyuki Tanaka ◽  
Yoshinori Matsuura ◽  
Hisashi Naitow ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Small Molecule ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
X Ray ◽  
X Ray Crystallography ◽  
Multiple Binding

scholarly journals A Chemical Probe Based on the PreQ1 Metabolite Enables Transcriptome-wide Mapping of Binding Sites

2021 ◽  
Author(s):  
Sumirtha Balaratnam ◽  
Curran Rhodes ◽  
Desta Bume ◽  
Colleen Connelly ◽  
Christopher Lai ◽  
...  
Keyword(s):  
Small Molecule ◽  
Binding Sites ◽  
X Ray ◽  
X Ray Crystallography ◽  
Rna Targets ◽  
Active Probe ◽  
Selective Interaction ◽  
Molecule Interactions ◽  
Competition Assays

Abstract The role of metabolite-responsive riboswitches in regulating gene expression in bacteria is well known and makes them useful systems for the study of RNA-small molecule interactions. Here, we study the PreQ1 riboswitch system, assessing sixteen diverse PreQ1-derived probes for their ability to selectively modify the riboswitch aptamer covalently. For the most active probe, a diazirine-based photocrosslinker, X-ray crystallography and gel-based competition assays demonstrated the mode of binding of the ligand to the aptamer, and functional assays demonstrated that the probe retains activity against the full riboswitch. Transcriptome-wide mapping using Chem-CLIP revealed a highly selective interaction between the bacterial aptamer and the small molecule. In addition, a small number of RNA targets in endogenous human transcripts were found to bind specifically to PreQ1, providing evidence for candidate PreQ1 aptamers in human RNA. This work demonstrates a stark influence of linker chemistry and structure on the ability of molecules to crosslink RNA, reveals that the PreQ1 aptamer/ligand pair are broadly useful for chemical biology applications, and provides insights into how PreQ1 interacts with human RNAs.

scholarly journals P3-293: Investigation of the critical amino acids in the BACE1 binding site that interact with small molecule inhibitors using a novel radioligand and X-ray crystallography

2009 ◽  
Vol 5 (4S_Part_14) ◽  
pp. P429-P429
Author(s):  
Warren D. Hirst ◽  
Katie Kubek ◽  
Jonathan Bard ◽  
James Turner ◽  
Kristi Fan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Binding Site ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
X Ray ◽  
X Ray Crystallography

Synthesis and coordination studies of new aminoalcohol functionalized tertiary phosphines

2001 ◽  
Vol 79 (5-6) ◽  
pp. 780-791 ◽  
Author(s):  
Sean E Durran ◽  
Martin B Smith ◽  
Alexandra MZ Slawin ◽  
Thomas Gelbrich ◽  
Michael B Hursthouse ◽  
...  
Keyword(s):  
Precious Metals ◽  
Nmr Studies ◽  
X Ray ◽  
X Ray Crystallography ◽  
Tertiary Phosphines ◽  
Linear Chains ◽  
Metal Precursors ◽  
I 11 ◽  
Late Transition ◽  
Hybrid Ligands

The synthesis of two new aminoalcohol functionalized tertiary phosphines o-Ph2PCH2N(H)C6H4(OH) (I) and o-Ph2PCH2N(H)C6H4(CH2OH) (II) are reported. Oxidation with aqueous H2O2 gave the corresponding phosphine oxides o-Ph2P(O)CH2N(H)C6H4(OH) (III) and o-Ph2P(O)CH2N(H)C6H4(CH2OH) (IV) (31P NMR evidence only). The ligating ability of I, II and, in several cases, the known ligand 2,3-Ph2PCH2N(H)C5H3N(OH) (V), was investigated with a range of late transition-metal precursors. Accordingly, reaction of 2 equiv of I (or II) with [MCl2(cod)] (M = Pd or Pt, cod = cycloocta-1,5-diene) gave the corresponding dichloro metal(II) complexes [MCl2(I)2] (M = Pd 1; M = Pt 2) and [MCl2(II)2] (M = Pd 3; M = Pt 4) in which I (and II) P-coordinate. Solution NMR studies reveal that 2 and 4 are exclusively cis whereas 1 and 3 are present as a mixture of cis and (or) trans isomers [4.7:1 (for 1); 2.2:1 (for 3)]. Reaction of 2 equiv of II with [Pt(CH3)2(cod)] gave the neutral complex [Pt(CH3)2(II)2] (5) whose X-ray structure confirmed a cis disposition of "hybrid" ligands. In contrast, reaction of I with [Pt(CH3)2(cod)] gave initially [Pt(CH3)2(I)2] (6) which, upon standing, afforded several products possibly reflecting an increased acidity of the phenolic groups of ligated I. Chloro bridge cleavage reactions of [{Ru(µ-Cl)Cl(p-cymene)}2] or [{Rh(µ-Cl)Cl{C5(CH3)5}}2] with I (or II) proceeds smoothly and gave the mononuclear complexes [RuCl2(p-cymene)I] (7), [RuCl2(p-cymene)II] (8), [RhCl2{C5(CH3)5}I] (9), and [RhCl2{C5(CH3)5}II] (10) in good yield. X-ray crystallography confirms both ruthenium complexes bear P-coordinated I (or II) ligands. Molecules of 7 are linked into linear chains via O-H···Clcoord intermolecular hydrogen bonding, a feature absent in the closely related compound 8. Reaction of [AuCl(tht)] (tht = tetrahydrothiophene) with 1 equiv of I (or II) gave the corresponding gold(I) complexes [AuCl(I)] (11) and [AuCl(II)] (12). Bridge cleavage of the cyclometallated palladium(II) dimers [{Pd(µ-Cl)(C~N)}2] [C~N = C,N-C6H4CH2N(CH3)2, C,N-C10H6N(CH3)2, C,N-C6H4N=NC6H5] with V (or I) gave the neutral complexes [PdCl(C~N)V] (13-15) (or [PdCl(C9H12N)I] (16)), respectively. Chloride abstraction from 13 (or 15) with Ag[BF4] gave the cationic complexes [Pd(C~N)V][BF4] (17) (or 18) in which V P,N pyridyl-chelates to the palladium(II) metal centre. The X-ray structures of 13 and 18 have been determined and confirm the expected coordination environments. An array of intra- and intermolecular H-bonding contacts are also observed. All compounds have been characterized by a combination of spectroscopic and analytical studies.Key words: phosphines, crystal structures, alcohols, precious metals.

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