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See detailMolecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.
Yeh, Tzu-Lan; Leissing, Thomas M.; Abboud, Martine I. et al

in Chemical science (2017), 8(11), 7651-7668

Inhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1-3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of ... [more ▼]

Inhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1-3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of therapeutic interest. We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities versus representatives of other human 2OG oxygenase subfamilies. The 'clinical' PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-alpha oxygen dependent degradation domains (ODDs), and selective against most, but not all, representatives of other human 2OG dependent dioxygenase subfamilies. Crystallographic and NMR studies provide insights into the different active site binding modes of the inhibitors. Cell-based results reveal the inhibitors have similar effects on the upregulation of HIF target genes, but differ in the kinetics of their effects and in extent of inhibition of hydroxylation of the N- and C-terminal ODDs; the latter differences correlate with the biophysical observations. [less ▲]

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See detailPowder diffraction and crystal structure prediction identify four new coumarin polymorphs
Shtukenberg, Alexander G.; Zhu, Qiang; Carter, Damien J. et al

in Chemical Science (2017)

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new ... [more ▼]

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and the need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects. [less ▲]

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See detailModeling quantum nuclei with perturbed path integral molecular dynamics
Poltavsky, Igor; Tkatchenko, Alexandre UL

in Chemical Science (2016), 7(2), 1368-1372

The quantum nature of nuclear motions plays a vital role in the structure, stability, and thermodynamics of molecules and materials. The standard approach to model nuclear quantum fluctuations in chemical ... [more ▼]

The quantum nature of nuclear motions plays a vital role in the structure, stability, and thermodynamics of molecules and materials. The standard approach to model nuclear quantum fluctuations in chemical and biological systems is to use path-integral molecular dynamics. Unfortunately, conventional path-integral simulations can have an exceedingly large computational cost due to the need to employ an excessive number of coupled classical subsystems (beads) for quantitative accuracy. Here, we combine perturbation theory with the Feynman-Kac imaginary-time path integral approach to quantum mechanics and derive an improved non-empirical partition function and estimators to calculate converged quantum observables. Our perturbed path-integral (PPI) method requires the same ingredients as the conventional approach but increases the accuracy and efficiency of path integral simulations by an order of magnitude. Results are presented for the thermodynamics of fundamental model systems, an empirical water model containing 256 water molecules within periodic boundary conditions, and ab initio simulations of nitrogen and benzene molecules. For all of these examples, PPI simulations with 4 to 8 classical beads recover the nuclear quantum contribution to the total energy and heat capacity at room temperature within a 3 accuracy, paving the way toward seamless modeling of nuclear quantum effects in realistic molecules and materials. [less ▲]

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See detailvan der Waals dispersion interactions in molecular materials: beyond pairwise additivity
Reilly, Anthony M.; Tkatchenko, Alexandre UL

in Chemical Science (2015), 6(6), 3289-3301

van der Waals (vdW) dispersion interactions are a key ingredient in the structure, stability, and response properties of many molecular materials and essential for us to be able to understand and design ... [more ▼]

van der Waals (vdW) dispersion interactions are a key ingredient in the structure, stability, and response properties of many molecular materials and essential for us to be able to understand and design novel intricate molecular systems. Pairwise-additive models of vdW interactions are ubiquitous, but neglect their true quantum-mechanical many-body nature. In this perspective we focus on recent developments and applications of methods that can capture collective and many-body effects in vdW interactions. Highlighting a number of recent studies in this area, we demonstrate both the need for and usefulness of explicit many-body treatments for obtaining qualitative and quantitative accuracy for modelling molecular materials, with applications presented for small-molecule dimers, supramolecular host-guest complexes, and finally stability and polymorphism in molecular crystals. [less ▲]

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See detail5-Carboxy-8-hydroxyquinoline is a Broad Spectrum 2-Oxoglutarate Oxygenase Inhibitor which Causes Iron Translocation.
Hopkinson, Richard J.; Tumber, Anthony; Yapp, Clarence et al

in Chemical Science (2013), 4(8), 3110-3117

2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline ... [more ▼]

2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors, N-oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and gamma-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement. [less ▲]

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