Rationalising the retro-Diels-Alder fragmentation pattern of viscutins using electrospray interface-tandem mass spectrometry coupled to theoretical modelling
- Moyo, Babra, Novokoza, Yolanda, Tavengwa, Nikita T, Kuhnert, Nikolai, Lobb, Kevin A, Madala, Ntakadzeni E
- Authors: Moyo, Babra , Novokoza, Yolanda , Tavengwa, Nikita T , Kuhnert, Nikolai , Lobb, Kevin A , Madala, Ntakadzeni E
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452786 , vital:75170 , xlink:href="https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/epdf/10.1002/rcm.9592"
- Description: Although mass spectrometry (MS) is a powerful tool in structural elucidation of unknown flavonoids based on their unique fragmentation patterns, proposing the correct fragmentation mechanism is still a challenge from tandem mass spectrometry data only. In recent years, computational tools such as molecular networking and MS2LDA have played a major role in the identification of structurally related compounds through an in-depth survey of their fragmentation patterns.
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- Authors: Moyo, Babra , Novokoza, Yolanda , Tavengwa, Nikita T , Kuhnert, Nikolai , Lobb, Kevin A , Madala, Ntakadzeni E
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452786 , vital:75170 , xlink:href="https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/epdf/10.1002/rcm.9592"
- Description: Although mass spectrometry (MS) is a powerful tool in structural elucidation of unknown flavonoids based on their unique fragmentation patterns, proposing the correct fragmentation mechanism is still a challenge from tandem mass spectrometry data only. In recent years, computational tools such as molecular networking and MS2LDA have played a major role in the identification of structurally related compounds through an in-depth survey of their fragmentation patterns.
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Drug Resistance in the HIV-1 Subtype C Protease Enzyme: A High Throughput Virtual Screening Approach in Search of New Ligands with Activity
- Sarron, Arthur F D, Lobb, Kevin A
- Authors: Sarron, Arthur F D , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452699 , vital:75163 , xlink:href="10.2174/1871520622666220202161543"
- Description: Background: HIV-1 subtype C protease is a strategic target for antiretroviral treatment. However, resistance to protease inhibi-tors appears after months of treatment. Chromones and 2- bis-coumarin derivatives show potential for inhibition of the HIV- subtype C protease. Objective: Different heterocyclic structures from the ZINC database were docked against Human Immuno-deficiency Virus-1 (HIV) subtype C protease crystal structure 2R5Q and 2R5P. The 5 best molecules were selected to be docked against 62 homology models based on HIV-protease se-quences from infants failing antiretroviral protease treatment. This experimentation was performed with two molecular docking programs: Autodock and Autodock Vina. These molecules were modified by substituting protons with different moieties, and the derivatives were docked against the same targets. Ligand-protein interactions, physical/chemical proprieties of the mole-cules, and dynamics simulations were analyzed.
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- Authors: Sarron, Arthur F D , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452699 , vital:75163 , xlink:href="10.2174/1871520622666220202161543"
- Description: Background: HIV-1 subtype C protease is a strategic target for antiretroviral treatment. However, resistance to protease inhibi-tors appears after months of treatment. Chromones and 2- bis-coumarin derivatives show potential for inhibition of the HIV- subtype C protease. Objective: Different heterocyclic structures from the ZINC database were docked against Human Immuno-deficiency Virus-1 (HIV) subtype C protease crystal structure 2R5Q and 2R5P. The 5 best molecules were selected to be docked against 62 homology models based on HIV-protease se-quences from infants failing antiretroviral protease treatment. This experimentation was performed with two molecular docking programs: Autodock and Autodock Vina. These molecules were modified by substituting protons with different moieties, and the derivatives were docked against the same targets. Ligand-protein interactions, physical/chemical proprieties of the mole-cules, and dynamics simulations were analyzed.
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Solvent promoted tautomerism in thione-containing tetraazatricyclics: evidence from 1H NMR spectroscopy and transition state studies
- Odame, Felix, Tshentu, Zenixole R, Lobb, Kevin A
- Authors: Odame, Felix , Tshentu, Zenixole R , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453198 , vital:75230 , xlink:href="https://link.springer.com/article/10.1007/s00894-022-05204-w"
- Description: Tautomerism in the nitro substituted thione-containing traazatricyclics has been investigated. Evidence from 1 H NMR indicating the existence of the tautomers has been augmented with computational studies providing evidence of the stability or otherwise of these tautomers. The role of water and DMSO in the formation of the tautomers has been explained. The role of the nitro group in assisting in the formation of the tautomers has been discussed.
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- Authors: Odame, Felix , Tshentu, Zenixole R , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453198 , vital:75230 , xlink:href="https://link.springer.com/article/10.1007/s00894-022-05204-w"
- Description: Tautomerism in the nitro substituted thione-containing traazatricyclics has been investigated. Evidence from 1 H NMR indicating the existence of the tautomers has been augmented with computational studies providing evidence of the stability or otherwise of these tautomers. The role of water and DMSO in the formation of the tautomers has been explained. The role of the nitro group in assisting in the formation of the tautomers has been discussed.
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The molecular basis of the effect of temperature on the structure and function of SARS-CoV-2 spike protein
- Khan, Faez I, Lobb, Kevin A, Lai, Dakun
- Authors: Khan, Faez I , Lobb, Kevin A , Lai, Dakun
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453223 , vital:75232 , xlink:href="https://doi.org/10.3389/fmolb.2022.794960"
- Description: The remarkable rise of the current COVID-19 pandemic to every part of the globe has raised key concerns for the current public healthcare system. The spike (S) protein of SARS-CoV-2 shows an important part in the cell membrane fusion and receptor recognition. It is a key target for vaccine production. Several researchers studied the nature of this protein under various environmental conditions. In this work, we applied molecular modeling and extensive molecular dynamics simulation approaches at 0°C (273.15 K), 20°C (293.15 K), 40°C (313.15 K), and 60°C (333.15 K) to study the detailed conformational alterations in the SARS-CoV-2 S protein. Our aim is to understand the influence of temperatures on the structure, function, and dynamics of the S protein of SARS-CoV-2. The structural deviations, and atomic and residual fluctuations were least at low (0°C) and high (60°C) temperature. Even the internal residues of the SARS-CoV-2 S protein are not accessible to solvent at high temperature. Furthermore, there was no unfolding of SARS-CoV-2 spike S reported at higher temperature. The most stable conformations of the SARS-CoV-2 S protein were reported at 20°C, but the free energy minimum region of the SARS-CoV-2 S protein was sharper at 40°C than other temperatures. Our findings revealed that higher temperatures have little or no influence on the stability and folding of the SARS-CoV-2 S protein.
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- Authors: Khan, Faez I , Lobb, Kevin A , Lai, Dakun
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453223 , vital:75232 , xlink:href="https://doi.org/10.3389/fmolb.2022.794960"
- Description: The remarkable rise of the current COVID-19 pandemic to every part of the globe has raised key concerns for the current public healthcare system. The spike (S) protein of SARS-CoV-2 shows an important part in the cell membrane fusion and receptor recognition. It is a key target for vaccine production. Several researchers studied the nature of this protein under various environmental conditions. In this work, we applied molecular modeling and extensive molecular dynamics simulation approaches at 0°C (273.15 K), 20°C (293.15 K), 40°C (313.15 K), and 60°C (333.15 K) to study the detailed conformational alterations in the SARS-CoV-2 S protein. Our aim is to understand the influence of temperatures on the structure, function, and dynamics of the S protein of SARS-CoV-2. The structural deviations, and atomic and residual fluctuations were least at low (0°C) and high (60°C) temperature. Even the internal residues of the SARS-CoV-2 S protein are not accessible to solvent at high temperature. Furthermore, there was no unfolding of SARS-CoV-2 spike S reported at higher temperature. The most stable conformations of the SARS-CoV-2 S protein were reported at 20°C, but the free energy minimum region of the SARS-CoV-2 S protein was sharper at 40°C than other temperatures. Our findings revealed that higher temperatures have little or no influence on the stability and folding of the SARS-CoV-2 S protein.
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Interaction of silver nanoparticles with catechol O-methyltransferase: Spectroscopic and simulation analyses
- Usman, Aminu, Lobb, Kevin A, Pletschke, Brett I, Whiteley, Christopher G, Wilhelmi, Brendan S
- Authors: Usman, Aminu , Lobb, Kevin A , Pletschke, Brett I , Whiteley, Christopher G , Wilhelmi, Brendan S
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451095 , vital:75018 , xlink:href=" https://doi.org/10.1016/j.bbrep.2021.101013"
- Description: Catechol O-methyltransferase, an enzyme involved in the metabolism of catechol containing compounds, catalyzes the transfer of a methyl group between S-adenosylmethionine and the hydroxyl groups of the catechol. Furthermore it is considered a potential drug target for Parkinson’s disease as it metabolizes the drug levodopa. Consequently inhibitors of the enzyme would increase levels of levodopa. In this study, absorption, fluorescence and infrared spectroscopy as well as computational simulation studies investigated human soluble catechol Omethyltransferase interaction with silver nanoparticles. The nanoparticles form a corona with the enzyme and quenches the fluorescence of Trp143. This amino acid maintains the correct structural orientation for the catechol ring during catalysis through a static mechanism supported by a non-fluorescent fluorophore–nanoparticle complex. The enzyme has one binding site for AgNPs in a thermodynamically spontaneous binding driven by electrostatic interactions as confirmed by negative ΔG and ΔH and positive ΔS values. Fourier transform infrared spectroscopy within the amide I region of the enzyme indicated that the interaction causes relaxation of its β− structures, while simulation studies indicated the involvement of six polar amino acids. These findings suggest AgNPs influence the catalytic activity of catechol O-methyltransferase, and therefore have potential in controlling the activity of the enzyme.
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- Authors: Usman, Aminu , Lobb, Kevin A , Pletschke, Brett I , Whiteley, Christopher G , Wilhelmi, Brendan S
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451095 , vital:75018 , xlink:href=" https://doi.org/10.1016/j.bbrep.2021.101013"
- Description: Catechol O-methyltransferase, an enzyme involved in the metabolism of catechol containing compounds, catalyzes the transfer of a methyl group between S-adenosylmethionine and the hydroxyl groups of the catechol. Furthermore it is considered a potential drug target for Parkinson’s disease as it metabolizes the drug levodopa. Consequently inhibitors of the enzyme would increase levels of levodopa. In this study, absorption, fluorescence and infrared spectroscopy as well as computational simulation studies investigated human soluble catechol Omethyltransferase interaction with silver nanoparticles. The nanoparticles form a corona with the enzyme and quenches the fluorescence of Trp143. This amino acid maintains the correct structural orientation for the catechol ring during catalysis through a static mechanism supported by a non-fluorescent fluorophore–nanoparticle complex. The enzyme has one binding site for AgNPs in a thermodynamically spontaneous binding driven by electrostatic interactions as confirmed by negative ΔG and ΔH and positive ΔS values. Fourier transform infrared spectroscopy within the amide I region of the enzyme indicated that the interaction causes relaxation of its β− structures, while simulation studies indicated the involvement of six polar amino acids. These findings suggest AgNPs influence the catalytic activity of catechol O-methyltransferase, and therefore have potential in controlling the activity of the enzyme.
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Benzimidazole or Diamide From a Reaction of Diamines and Carboxylic Acids or Acid Chlorides: Crystal Structures and Theoretical Studies
- Odame, Felix, Hosten, Eric C, Betz, Richard, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447938 , vital:74685 , xlink:href="https://pdfs.semanticscholar.org/bf5a/ce94c9436f40059793eb988e08da8ef09886.pdf"
- Description: A reaction of an acid chloride with a diamine yielded a diamide. m-Toluic acid was chlorinated to m-toluoyl chloride and subsequently reacted with 4-methyl-o-phenylenediamine in pyridine to obtain 3-methyl-N-[2-(3-methylbenzamido)phenylbenzamide (I). 2-(3-Methylphenyl)-1H-benzimidazole (II) has been obtained upon reacting o-phenylenediamine with m-toluic acid in polyphosphoric acid and toluene. The compounds have been characterized by IR, NMR, microanalyses and GC-MS. The crystal structures of the compounds have been discussed. DFT calculations of the frontier orbitals of the precursor compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity in the formation of the diamides and benzimidazoles. The synthesis of the amide from a diamine was seen to be favoured in the presence of a good leaving group attached to the carbonyl as in the case of acid chloride. However, the synthesis of benzimidazoles was found to be favoured in the presence of an excess of a protonating agent and high temperature.
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- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447938 , vital:74685 , xlink:href="https://pdfs.semanticscholar.org/bf5a/ce94c9436f40059793eb988e08da8ef09886.pdf"
- Description: A reaction of an acid chloride with a diamine yielded a diamide. m-Toluic acid was chlorinated to m-toluoyl chloride and subsequently reacted with 4-methyl-o-phenylenediamine in pyridine to obtain 3-methyl-N-[2-(3-methylbenzamido)phenylbenzamide (I). 2-(3-Methylphenyl)-1H-benzimidazole (II) has been obtained upon reacting o-phenylenediamine with m-toluic acid in polyphosphoric acid and toluene. The compounds have been characterized by IR, NMR, microanalyses and GC-MS. The crystal structures of the compounds have been discussed. DFT calculations of the frontier orbitals of the precursor compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity in the formation of the diamides and benzimidazoles. The synthesis of the amide from a diamine was seen to be favoured in the presence of a good leaving group attached to the carbonyl as in the case of acid chloride. However, the synthesis of benzimidazoles was found to be favoured in the presence of an excess of a protonating agent and high temperature.
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Synthesis and MRSA PK inhibitory activity of thiazole containing deoxytopsentin analogues
- Veale, Clinton G L, Lobb, Kevin A, Zoraghi, Roya, Morrison, James P, Reiner, Neil E, Andersen, Raymond J, Davies-Coleman, Michael T
- Authors: Veale, Clinton G L , Lobb, Kevin A , Zoraghi, Roya , Morrison, James P , Reiner, Neil E , Andersen, Raymond J , Davies-Coleman, Michael T
- Date: 2014
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448028 , vital:74692 , xlink:href="https://doi.org/10.1016/j.tet.2014.09.007"
- Description: The public health care crisis caused by the emergence of drug resistant bacterial strains, e.g., methicillin resistant Staphylococcus aureus (MRSA) has underlined the urgent need to accelerate the discovery of new chemical entities active against antibiotic resistant bacteria. We report here the synthesis of a series thiazole containing deoxytopsentin analogues, which show moderate activity against a target MRSA pyruvate kinase enzyme: an evolutionary conserved hub protein critical for bacterial survival. A Hantzsch thiazole coupling between a-oxo-1H-indole-3-thioacetamides and 2-bromo-1-(1H-indol-3-yl)-ethanones provided facile access to the thiazole containing deoxytopsentin compounds.
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- Authors: Veale, Clinton G L , Lobb, Kevin A , Zoraghi, Roya , Morrison, James P , Reiner, Neil E , Andersen, Raymond J , Davies-Coleman, Michael T
- Date: 2014
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448028 , vital:74692 , xlink:href="https://doi.org/10.1016/j.tet.2014.09.007"
- Description: The public health care crisis caused by the emergence of drug resistant bacterial strains, e.g., methicillin resistant Staphylococcus aureus (MRSA) has underlined the urgent need to accelerate the discovery of new chemical entities active against antibiotic resistant bacteria. We report here the synthesis of a series thiazole containing deoxytopsentin analogues, which show moderate activity against a target MRSA pyruvate kinase enzyme: an evolutionary conserved hub protein critical for bacterial survival. A Hantzsch thiazole coupling between a-oxo-1H-indole-3-thioacetamides and 2-bromo-1-(1H-indol-3-yl)-ethanones provided facile access to the thiazole containing deoxytopsentin compounds.
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Characterization of nickel tetrahydroxy phthalocyanine complexes and the electrocatalytic oxidation of 4-chlorophenol
- Khene, Samson M, Lobb, Kevin A, Nyokong, Tebello
- Authors: Khene, Samson M , Lobb, Kevin A , Nyokong, Tebello
- Date: 2009
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/263308 , vital:53616 , xlink:href="https://doi.org/10.1016/j.ica.2009.08.019"
- Description: This work reports on the use of nickel(II) tetrahydroxy (NiPc(OH)4) and (poly-Ni(OH)Pc(OH)4) phthalocyanine complexes as films on ordinary poly graphite electrode (OPGE) for the electrochemical oxidation of 4-chlorophenol (4-CP). The NiPc(OH)4 film was electrotransformed to Ni(OH)Pc(OH)4 film in aqueous 0.1 M NaOH solution to the ‘O–Ni–O oxo’ bridge form. The result showed that the Ni(OH)Pc(OH)4 film on OPGE was more electroactive in terms of increase in current and less catalytic in terms of potential compared to the adsorbed NiPc(OH)4 on OPGE. The reactivity of the two molecules was explained by theoretical calculations. The energies of the frontier orbitals of NiPc(OH)4, Ni(OH)Pc(OH)4 and 4-chlorophenol were calculated using density functional theory (DFT) method. The inter molecular hardness (η) and donor–acceptor hardness (ηDA) of Ni(OH)Pc(OH)4, NiPc(OH)4, Ni(OH)Pc(OH)4/4-chlorophenol and NiPc(OH)4/4-chlorophenol were estimated. The Ni(OH)Pc(OH)4, showed stronger interaction with 4-chlorophenol than NiPc(OH)4. DFT method was also used to model IR and Raman spectrum of H2Pc(OH)4 and NiPc(OH)4.
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- Authors: Khene, Samson M , Lobb, Kevin A , Nyokong, Tebello
- Date: 2009
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/263308 , vital:53616 , xlink:href="https://doi.org/10.1016/j.ica.2009.08.019"
- Description: This work reports on the use of nickel(II) tetrahydroxy (NiPc(OH)4) and (poly-Ni(OH)Pc(OH)4) phthalocyanine complexes as films on ordinary poly graphite electrode (OPGE) for the electrochemical oxidation of 4-chlorophenol (4-CP). The NiPc(OH)4 film was electrotransformed to Ni(OH)Pc(OH)4 film in aqueous 0.1 M NaOH solution to the ‘O–Ni–O oxo’ bridge form. The result showed that the Ni(OH)Pc(OH)4 film on OPGE was more electroactive in terms of increase in current and less catalytic in terms of potential compared to the adsorbed NiPc(OH)4 on OPGE. The reactivity of the two molecules was explained by theoretical calculations. The energies of the frontier orbitals of NiPc(OH)4, Ni(OH)Pc(OH)4 and 4-chlorophenol were calculated using density functional theory (DFT) method. The inter molecular hardness (η) and donor–acceptor hardness (ηDA) of Ni(OH)Pc(OH)4, NiPc(OH)4, Ni(OH)Pc(OH)4/4-chlorophenol and NiPc(OH)4/4-chlorophenol were estimated. The Ni(OH)Pc(OH)4, showed stronger interaction with 4-chlorophenol than NiPc(OH)4. DFT method was also used to model IR and Raman spectrum of H2Pc(OH)4 and NiPc(OH)4.
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