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Isomeric and Conformational Analysis of Small Drug and Drug-Like Molecules by Ion Mobility-Mass Spectrometry (IM-MS).
Phillips ST, Dodds JN, May JC, McLean JA
(2019) Methods Mol Biol 1939: 161-178
MeSH Terms: Algorithms, Amino Acids, Carbohydrates, Ion Mobility Spectrometry, Isomerism, Mass Spectrometry, Molecular Conformation, Pharmaceutical Preparations, Small Molecule Libraries, Software
Show Abstract · Added August 7, 2019
This chapter provides a broad overview of ion mobility-mass spectrometry (IM-MS) and its applications in separation science, with a focus on pharmaceutical applications. A general overview of fundamental ion mobility (IM) theory is provided with descriptions of several contemporary instrument platforms which are available commercially (i.e., drift tube and traveling wave IM). Recent applications of IM-MS toward the evaluation of structural isomers are highlighted and placed in the context of both a separation and characterization perspective. We conclude this chapter with a guided reference protocol for obtaining routine IM-MS spectra on a commercially available uniform-field IM-MS.
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Ion mobility conformational lipid atlas for high confidence lipidomics.
Leaptrot KL, May JC, Dodds JN, McLean JA
(2019) Nat Commun 10: 985
MeSH Terms: Animals, Databases, Chemical, Lipids, Mass Spectrometry, Metabolomics, Molecular Conformation, Molecular Structure
Show Abstract · Added August 7, 2019
Lipids are highly structurally diverse molecules involved in a wide variety of biological processes. Here, we use high precision ion mobility-mass spectrometry to compile a structural database of 456 mass-resolved collision cross sections (CCS) of sphingolipid and glycerophospholipid species. Our CCS database comprises sphingomyelin, cerebroside, ceramide, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phosphatidic acid classes. Primary differences observed are between lipid categories, with sphingolipids exhibiting 2-6% larger CCSs than glycerophospholipids of similar mass, likely a result of the sphingosine backbone's restriction of the sn1 tail length, limiting gas-phase packing efficiency. Acyl tail length and degree of unsaturation are found to be the primary structural descriptors determining CCS magnitude, with degree of unsaturation being four times as influential per mass unit. The empirical CCS values and previously unmapped quantitative structural trends detailed in this work are expected to facilitate prediction of CCS in broadscale lipidomics research.
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Movement of the RecG Motor Domain upon DNA Binding Is Required for Efficient Fork Reversal.
Warren GM, Stein RA, Mchaourab HS, Eichman BF
(2018) Int J Mol Sci 19:
MeSH Terms: DNA, DNA Helicases, DNA Replication, DNA-Binding Proteins, Models, Molecular, Molecular Conformation, Mutation, Nucleic Acid Conformation, Protein Binding, Protein Interaction Domains and Motifs, Structure-Activity Relationship
Show Abstract · Added August 26, 2019
RecG catalyzes reversal of stalled replication forks in response to replication stress in bacteria. The protein contains a fork recognition ("wedge") domain that binds branched DNA and a superfamily II (SF2) ATPase motor that drives translocation on double-stranded (ds)DNA. The mechanism by which the wedge and motor domains collaborate to catalyze fork reversal in RecG and analogous eukaryotic fork remodelers is unknown. Here, we used electron paramagnetic resonance (EPR) spectroscopy to probe conformational changes between the wedge and ATPase domains in response to fork DNA binding by RecG. Upon binding DNA, the ATPase-C lobe moves away from both the wedge and ATPase-N domains. This conformational change is consistent with a model of RecG fully engaged with a DNA fork substrate constructed from a crystal structure of RecG bound to a DNA junction together with recent cryo-electron microscopy (EM) structures of chromatin remodelers in complex with dsDNA. We show by mutational analysis that a conserved loop within the translocation in RecG (TRG) motif that was unstructured in the RecG crystal structure is essential for fork reversal and DNA-dependent conformational changes. Together, this work helps provide a more coherent model of fork binding and remodeling by RecG and related eukaryotic enzymes.
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Absolute configuration of an axially chiral sulfonate determined from its optical rotatory dispersion, electronic circular dichroism, and vibrational circular dichroism spectra.
Covington CL, Raghavan V, Smuts JP, Armstrong DW, Polavarapu PL
(2017) Chirality 29: 670-676
MeSH Terms: Circular Dichroism, Models, Molecular, Molecular Conformation, Naphthalenes, Optical Rotatory Dispersion, Stereoisomerism, Sulfonic Acids, Vibration
Show Abstract · Added April 10, 2018
The absolute configuration (AC) of an axially chiral sulfonate (aCSO), 3,5-dimethyl-2-(naphthalen-1-yl)-6-(naphthalen-1-yl)benzenesulfonate (labeled as aCSO5), was investigated using optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectroscopies. All three methods led to the same conclusion and the AC of aCSO5 is reliably determined to be (-)-(aR, aR), or conversely (+)-(aS, aS).
© 2017 Wiley Periodicals, Inc.
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8 MeSH Terms
Investigation of the Complete Suite of the Leucine and Isoleucine Isomers: Toward Prediction of Ion Mobility Separation Capabilities.
Dodds JN, May JC, McLean JA
(2017) Anal Chem 89: 952-959
MeSH Terms: Isoleucine, Isomerism, Leucine, Mass Spectrometry, Molecular Conformation
Show Abstract · Added December 17, 2018
In this study we investigated 11 isomers with the molecular formula CHNO (m/z 131) to ascertain the potential of utilizing drift tube ion mobility mass spectrometry to aid in the separation of isomeric mixtures. This study of small molecules provides a detailed examination of the application of uniform field ion mobility for a narrow scope of isomers with variations in both bond coordination and stereochemistry. For small molecules, it was observed that in general constitutional isomers are more readily separated by uniform field mobility in comparison to stereoisomers such as enantiomers or diastereomers. Diastereomers exhibited differences in their collision cross section (CCS), but were unresolvable in a mixture, whereas the enantiomers studied did not exhibit statistically different CCS values. A mathematical relationship relating the CCS to resolving power was developed in order to predict the required ion mobility resolving power needed to separate the various isomer classes. For the majority of isomers evaluated in this study, a uniform field-based resolving power of 100 was predicted to be sufficient to resolve over half (∼60%) of all hypothetical isomer pairs, including leucine and isoleucine, whereas their stereoisomers (d- and l-forms) are predicted to be significantly more challenging, if not impossible, to separate by conventional drift tube techniques.
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Atropoisomerism in Biflavones: The Absolute Configuration of (-)-Agathisflavone via Chiroptical Spectroscopy.
Covington CL, Junior FM, Silva JH, Kuster RM, de Amorim MB, Polavarapu PL
(2016) J Nat Prod 79: 2530-2537
MeSH Terms: Biflavonoids, Circular Dichroism, Molecular Conformation, Molecular Structure, Optical Rotatory Dispersion, Stereoisomerism
Show Abstract · Added April 10, 2018
The first natural occurrence in optically active form of the dimeric flavonoid agathisflavone and definition of its axial chirality using chiroptical spectroscopic methods are described. The experimental electronic circular dichroism, electronic dissymmetry factor, optical rotatory dispersion, vibrational circular dichroism (VCD), and vibrational dissymmetry factor spectra of agathisflavone are presented and analyzed with their corresponding quantum chemical predictions to definitively assign the axial chirality of (-)-agathisflavone as (aS).
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Six Germline Genetic Variations Impair the Translesion Synthesis Activity of Human DNA Polymerase κ.
Kim JK, Yeom M, Hong JK, Song I, Lee YS, Guengerich FP, Choi JY
(2016) Chem Res Toxicol 29: 1741-1754
MeSH Terms: DNA-Directed DNA Polymerase, Genetic Variation, Humans, Models, Molecular, Molecular Conformation
Show Abstract · Added March 14, 2018
DNA polymerase (pol) κ efficiently catalyzes error-free translesion DNA synthesis (TLS) opposite bulky N-guanyl lesions induced by carcinogens such as polycyclic aromatic hydrocarbons. We investigated the biochemical effects of nine human nonsynonymous germline POLK variations on the TLS properties of pol κ, utilizing recombinant pol κ (residues 1-526) enzymes and DNA templates containing an N-CH(9-anthracenyl)G (N-AnthG), 8-oxo-7,8-dihydroguanine (8-oxoG), O-methyl(Me)G, or an abasic site. In steady-state kinetic analyses, the R246X, R298H, T473A, and R512W variants displayed 7- to 18-fold decreases in k/K for dCTP insertion opposite G and N-AnthG, with 2- to 3-fold decreases in DNA binding affinity, compared to that of the wild-type, and further showed 5- to 190-fold decreases in k/K for next-base extension from C paired with N-AnthG. The A471V variant showed 2- to 4-fold decreases in k/K for correct nucleotide insertion opposite and beyond G (or N-AnthG) compared to that of the wild-type. These five hypoactive variants also showed similar patterns of attenuation of TLS activity opposite 8-oxoG, O-MeG, and abasic lesions. By contrast, the T44M variant exhibited 7- to 11-fold decreases in k/K for dCTP insertion opposite N-AnthG and O-MeG (as well as for dATP insertion opposite an abasic site) but not opposite both G and 8-oxoG, nor beyond N-AnthG, compared to that of the wild-type. These results suggest that the R246X, R298H, T473A, R512W, and A471V variants cause a general catalytic impairment of pol κ opposite G and all four lesions, whereas the T44M variant induces opposite lesion-dependent catalytic impairment, i.e., only opposite O-MeG, abasic, and bulky N-G lesions but not opposite G and 8-oxoG, in pol κ, which might indicate that these hypoactive pol κ variants are genetic factors in modifying individual susceptibility to genotoxic carcinogens in certain subsets of populations.
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5 MeSH Terms
Investigating the Structure of Multicomponent Gel-Phase Lipid Bilayers.
Hartkamp R, Moore TC, Iacovella CR, Thompson MA, Bulsara PA, Moore DJ, McCabe C
(2016) Biophys J 111: 813-823
MeSH Terms: Gels, Hydrogen Bonding, Lipid Bilayers, Models, Molecular, Molecular Conformation, Water
Show Abstract · Added May 3, 2017
Single- and multicomponent lipid bilayers of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC), isostearyl isostearate, and heptadecanoyl heptadecanoate in the gel phase are studied via molecular dynamics simulations. It is shown that the structural properties of multicomponent bilayers can deviate strongly from the structures of their single-component counterparts. Specifically, the lipid mixtures are shown to adopt a compact packing by offsetting the positioning depths at which different lipid species are located in the bilayer. This packing mechanism affects the area per lipid, the bilayer height, and the chain tilt angles and has important consequences for other bilayer properties, such as interfacial hydrogen bonding and bilayer permeability. In particular, the simulations suggest that bilayers containing isostearyl isostearate or heptadecanoyl heptadecanoate are less permeable than pure 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine or DSPC bilayers. Furthermore, hydrogen-bond analysis shows that the residence times of lipid-water hydrogen bonds depend strongly on the bilayer composition, with longer residence times for bilayers that have a higher DSPC content. The findings illustrate and explain the fundamental differences between the properties of single- and multicomponent bilayers.
Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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6 MeSH Terms
Determination of the Absolute Configurations of Chiral Drugs Using Chiroptical Spectroscopy.
Polavarapu PL
(2016) Molecules 21:
MeSH Terms: Drug Design, Models, Molecular, Molecular Conformation, Spectrum Analysis
Show Abstract · Added April 10, 2018
Chiroptical spectroscopy has emerged as a promising tool for the determination of absolute configurations and predominant conformations of chiral molecules in academic laboratories. This promise has led to the adaption of chiroptical spectroscopic methods as valuable tools in chiral drug discovery research programs of the pharmaceutical industry. Most major pharmaceutical companies have invested in in-house chiroptical spectroscopy applications and reported successful outcomes. In the context of continuously increasing applications of chiroptical spectroscopy for chiral molecular structure determination, a review of recent developments and applications for chiral drugs is presented in this manuscript.
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Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics.
Garcia-Barrantes PM, Cho HP, Niswender CM, Byers FW, Locuson CW, Blobaum AL, Xiang Z, Rook JM, Conn PJ, Lindsley CW
(2015) J Med Chem 58: 7959-71
MeSH Terms: Animals, Central Nervous System, Epilepsy, GABA Agonists, GABA Modulators, Half-Life, Humans, Molecular Conformation, Rats, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Schizophrenia, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
The therapeutic potential of selective mGlu1 activation is vastly unexplored relative to the other group I mGlu receptor, mGlu5; therefore, our lab has focused considerable effort toward developing mGlu1 positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu1 PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu1 EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (Kp) of 1.02) mGlu1 PAM tool compound, that potentiated not only wild-type human mGlu1 but also mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu1 ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu5 ago-PAMs/PAMs and maintain temporal activity suggesting a broader therapeutic window.
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13 MeSH Terms