ORCID Profile
0000-0002-3366-7149
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Chemical Society (ACS)
Date: 29-12-2005
DOI: 10.1021/JM049438Q
Publisher: Springer Science and Business Media LLC
Date: 29-05-2012
Publisher: Elsevier BV
Date: 02-2008
Publisher: Elsevier BV
Date: 02-2009
Publisher: eLife Sciences Publications, Ltd
Date: 03-2018
DOI: 10.7554/ELIFE.32822
Abstract: The website Sci-Hub enables users to download PDF versions of scholarly articles, including many articles that are paywalled at their journal’s site. Sci-Hub has grown rapidly since its creation in 2011, but the extent of its coverage has been unclear. Here we report that, as of March 2017, Sci-Hub’s database contains 68.9% of the 81.6 million scholarly articles registered with Crossref and 85.1% of articles published in toll access journals. We find that coverage varies by discipline and publisher, and that Sci-Hub preferentially covers popular, paywalled content. For toll access articles, we find that Sci-Hub provides greater coverage than the University of Pennsylvania, a major research university in the United States. Green open access to toll access articles via licit services, on the other hand, remains quite limited. Our interactive browser at greenelab.github.io/scihub allows users to explore these findings in more detail. For the first time, nearly all scholarly literature is available gratis to anyone with an Internet connection, suggesting the toll access business model may become unsustainable.
Publisher: Springer Science and Business Media LLC
Date: 10-10-2023
Publisher: Cold Spring Harbor Laboratory
Date: 03-04-2020
DOI: 10.1101/2020.04.01.020883
Abstract: In its crystal structure in complex with the μ opioid receptor (μOR), the opioid BU72 exhibits extreme deviations from the expected geometry. 1 Three of these involve the phenyl group. There is also unexplained electron density next to the benzylic carbon. Here I show that inverting the benzylic configuration fills this unexplained density and eliminates the phenyl group outliers, along with all but one of the others. I propose that this is the correct structure of BU72.
Publisher: Wiley
Date: 18-07-2007
DOI: 10.1002/MRC.2020
Publisher: Elsevier BV
Date: 08-2013
Publisher: eLife Sciences Publications, Ltd
Date: 07-02-2018
Publisher: American Chemical Society (ACS)
Date: 11-12-2020
DOI: 10.26434/CHEMRXIV.13358786.V1
Abstract: In the crystal structure of BU72 bound to the μ opioid receptor, the opioid clashes with an adjacent residue, and unexplained electron density connects the two. It has been reported that this density can be filled by a magnesium ion. However, this proposal requires unrealistically short bonds and an incomplete coordination shell. Moreover, the crystals were prepared without magnesium salts, but with components that can generate reactive oxygen species: HEPES buffer, nickel ions, and an N-terminus that forms redox-active nickel complexes. Here I show that an oxygen atom fills the unexplained density, giving a known type of covalent adduct with reasonable geometry and no clashes. Strain is evident, but is consistent with tension from the tethered N-terminus.
Publisher: Public Library of Science (PLoS)
Date: 14-08-2013
Publisher: American Chemical Society (ACS)
Date: 29-06-2009
Publisher: American Chemical Society (ACS)
Date: 12-12-2022
DOI: 10.26434/CHEMRXIV-2022-GBRQH-V4
Abstract: Background The first crystal structure of the active μ opioid receptor (μOR) exhibited several unexplained features. The ligand BU72 exhibited many extreme deviations from ideal geometry, along with unexplained electron density around the benzylic carbon. I previously showed that inverting the benzylic configuration resolved these problems, establishing revised stereochemistry of BU72 and its analog BU74. However, another problem remains unresolved: additional unexplained electron density contacts both BU72 and a histidine residue in the N-terminus. Results Here I show that these short contacts and uninterrupted density are inconsistent with non-covalent interactions. Therefore, BU72 and μOR form a covalent adduct through an unmodeled atom, and the published model as two separate entities is incorrect. A subsequently proposed magnesium complex is also inconsistent with multiple lines of evidence. However, oxygen fits the unexplained density well. While the structure I propose is tentative, similar oxygen-bridged adducts have been reported previously in the presence of reactive oxygen species. Moreover, known sources of reactive oxygen species were present: HEPES buffer, nickel ions, and a sequence motif that forms redox-active nickel complexes. This motif contacts the unexplained density. The adduct exhibits severe strain, and the tethered N-terminus forms contacts with adjacent residues. These forces, along with the nanobody used as a G protein substitute, would be expected to influence the receptor conformation. Consistent with this, the intracellular end of the structure differs markedly from subsequent structures of active μOR bound to Gi protein. Conclusions Later Gi-bound structures are likely to be more accurate templates for docking and molecular dynamics simulations of active μOR. The possibility of reactions like this should be considered in the choice of protein truncation sites and purification conditions, and in the interpretation of excess or unexplained density.
Publisher: American Chemical Society (ACS)
Date: 09-02-2021
DOI: 10.26434/CHEMRXIV.13358786.V2
Abstract: In the crystal structure of BU72 bound to the μ opioid receptor (μOR), the opioid clashes with an adjacent residue in the N-terminus strong and unexplained electron density connects the two, centered on a point ~1.6 Å from each. This is too short for non-covalent interactions, implying covalent bonds to an unmodeled non-hydrogen atom. A magnesium ion has recently been proposed as a candidate. However, this would require unrealistically short bonds and an incomplete coordination shell. Moreover, the crystals were prepared without magnesium salts, but with components that can generate reactive oxygen species (ROS): HEPES buffer, nickel ions, and an N-terminus that forms redox-active nickel complexes. Here I show that an oxygen atom fits the unexplained density well, giving a type of covalent adduct known to form in the presence of ROS, with reasonable geometry and no clashes. While the precise structure is tentative, the observed density firmly establishes covalent bonds linking ligand and residue. Severe strain is evident in the ligand, the tethered N-terminus, and the connecting bonds. This strain, along with interactions between the N-terminus and surrounding residues, is likely to distort the receptor conformation. The subsequent μOR-Gi structure, which differs in several features associated with activation, is therefore likely to be a more accurate model of the active receptor. The possibility of reactions like this should be considered in the choice of protein truncation sites and purification conditions.
Publisher: Beilstein Institut
Date: 09-01-2007
Publisher: International Union of Crystallography (IUCr)
Date: 27-10-2012
Publisher: American Chemical Society (ACS)
Date: 18-04-2003
DOI: 10.1021/NP0205699
Abstract: Three new neoclerodane diterpenoids, salvinorins D-F (4-6), have been isolated from the leaves of Salvia inorum. The structures were elucidated by chemical and spectroscopic methods, particularly 1D and 2D NMR. A simplified isolation method using chromatography on activated carbon also gave improved yields of the controlled substance salvinorin A (1) and of salvinorin C (3).
Publisher: American Chemical Society (ACS)
Date: 11-2005
DOI: 10.1021/JO051813E
Publisher: No publisher found
Date: 2011
Publisher: Wiley
Date: 15-09-2017
DOI: 10.1002/EAT.22776
Abstract: This study aimed to examine the trajectory of symptom remission and affective functioning throughout the course of two family-based treatments for adolescent anorexia nervosa (AN): conjoint family-based treatment (FBT) and parent-focused treatment (PFT). Participants were 107 adolescents (M Multilevel models revealed increases in weight (β = 0.33, p < .001) and positive affect (β = 0.03, p < .001), and decreases in dietary restraint (β = -0.03, p < .001) and negative affect (β = -0.04, p < .001) over the course of treatment. No significant effects emerged by treatment type. These findings suggest that PFT may bring about comparable trajectories of weight gain and reduced dietary restraint as conjoint FBT, despite adolescents not being directly involved in treatment. These findings also highlight that the exclusively behavioral focus throughout both PFT and FBT is associated with significant increments in positive affect and significant reductions in negative affect.
Publisher: Beilstein Institut
Date: 20-12-2013
DOI: 10.3762/BJOC.9.328
Abstract: The recent crystal structure of the κ-opioid receptor (κ-OR) revealed, unexpectedly, that the antagonist JDTic is a bivalent ligand: in addition to the orthosteric pocket occupied by morphinans, JDTic also occupies a distinct (allotopic) pocket. Mutagenesis data suggest that salvinorin A ( 1 ) also binds to this allotopic pocket, adjacent to the aspartate residue that anchors the basic nitrogen atom of classical opiates (Asp138). It has been suggested that an H-bond donor appended to 1 might interact with Asp138, increasing affinity. Such a bivalent ligand might also possess altered functional selectivity. Based on modeling and known N -furanylmethyl opioid antagonists, we appended H-bond donors to the furan ring of 1 . (Dimethylamino)methyl groups at C-15 or C-16 abolished affinity for κ-OR. Hydroxymethylation at C-16 was tolerated, but 15,16-bis-hydroxymethylation was not. Since allosteric modulators may go undetected in binding assays, we also tested these and other low-affinity derivatives of 1 for allosteric modulation of dynorphin A in the [ 35 S]GTPγS assay. No modulation was detected. As an alternative attachment point for bivalent derivatives, we prepared the 2-(hydroxyethoxy)methyl ether, which retained high affinity for κ-OR. We discuss alternative design strategies for linked, fused or merged bivalent derivatives of 1 .
Publisher: American Chemical Society (ACS)
Date: 20-08-2003
DOI: 10.1021/NP030313I
Abstract: Three new neoclerodane diterpenoids, inatorins A-C (7-9), have been isolated from the leaves of Salvia inorum. The compounds were identified by spectroscopic methods as derivatives of the antibiotic (-)-hardwickiic acid (10), which was also isolated, along with four other known terpenoids. Neither the crude extract nor 7-9 displayed antimicrobial activity.
Publisher: Springer Science and Business Media LLC
Date: 08-12-2010
Publisher: Elsevier BV
Date: 09-2009
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 19-10-2007
Abstract: Several preclinical studies indicate that selective kappa-opioid receptor (KOR) antagonists have antidepressant-like effects, whereas KOR agonists have opposite effects, suggesting that each might be useful in the treatment of mood abnormalities. Salvinorin A (salvA) is a valuable KOR agonist for further study due to its high potency and receptor selectivity. However, it has short lasting effects in vivo and limited oral bioavailability, probably due to acetate metabolism. We compared the in vitro receptor binding selectivity of salvA and four analogs containing an ethyl ether (EE), isopropylamine (IPA), N-methylacetamide (NMA), or N-methylpropionamide (NMP) at C-2. All compounds showed high binding affinity for the KOR (K(i) = 0.11-6.3 nM), although only salvA, EE, and NMA exhibited KOR selectivity. In a liver microsomal assay, salvA was least stable, whereas NMA and IPA displayed slower metabolic transformations. Intraperitoneal (i.p.) administration of salvA, NMA, and NMP dose-dependently elevated brain reward thresholds in the intracranial self-administration (ICSS) test, consistent with prodepressive-like KOR agonist effects. NMA and NMP were equipotent to salvA but displayed longer lasting effects (6- and 10-fold, respectively). A dose of salvA with prominent effects in the ICSS test after i.p. administration (2.0 mg/kg) was inactive after oral administration, whereas the same oral dose of NMA elevated ICSS thresholds. These studies suggest that, although salvA and NMA are similar in potency and selectivity as KOR agonists in vitro, NMA has improved stability and longer lasting actions that might make it more useful for studies of KOR agonist effects in animals and humans.
Location: United States of America
No related grants have been discovered for Thomas Munro.