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.
- Full Text:
- Date Issued: 2009
- 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.
- Full Text:
- Date Issued: 2009
Theoretical and photodynamic therapy characteristics of heteroatom doped detonation nanodiamonds linked to asymmetrical phthalocyanine for eradication of breast cancer cells
- Matshitse, Refilwe, Tshiwawa, Tendamudzimu, Managa, Muthumuni, Nwaji, Njemuwa, Lobb, Kevin A, Nyokong, Tebello
- Authors: Matshitse, Refilwe , Tshiwawa, Tendamudzimu , Managa, Muthumuni , Nwaji, Njemuwa , Lobb, Kevin A , Nyokong, Tebello
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/186089 , vital:44462 , xlink:href="https://doi.org/10.1016/j.jlumin.2020.117465"
- Description: An amide mono substituted benzothiozole phthalocyanine: zinc(II) 3-(4-((3,17,23-tris(4-(benzo [d]thiazol-2-yl)phenoxy)-9-yl)oxy) phenyl)amide phthalocyanine (NH2BzPc) was covalently linked to undoped and heteroatom doped detonation nanodiamonds (DNDs): B@DNDs, P@DNDs, S@DNDs, N@DNDs, and SandN@DNDs There is a drastic decrease in highest occupied molecular orbital (HOMO) – lowest unoccupied molecular orbital (LUMO) energy gaps for nanoconjugates compared to DNDs alone. B@DNDs-NH2BzPc, SandN@DNDs-NH2BzPc, and P@DNDs-NH2BzPc showed superior photodynamic therapy (PDT) effects. DNDs-NH2BzPc also had a small HOMO-LUMO gap, but did not show improved PDT activity compared to the Pc alone, suggesting doping of DNDs is important. This study shows improved PDT effect on Michigan Cancer Foundation-7 breast cancer lines at 7.63%, 7.62% and 6.5% cell viability for P@DNDs-NH2BzPc, SandN@DNDs-NH2BzPc and B@DNDs-NH2BzPc, respectively.
- Full Text:
- Date Issued: 2020
- Authors: Matshitse, Refilwe , Tshiwawa, Tendamudzimu , Managa, Muthumuni , Nwaji, Njemuwa , Lobb, Kevin A , Nyokong, Tebello
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/186089 , vital:44462 , xlink:href="https://doi.org/10.1016/j.jlumin.2020.117465"
- Description: An amide mono substituted benzothiozole phthalocyanine: zinc(II) 3-(4-((3,17,23-tris(4-(benzo [d]thiazol-2-yl)phenoxy)-9-yl)oxy) phenyl)amide phthalocyanine (NH2BzPc) was covalently linked to undoped and heteroatom doped detonation nanodiamonds (DNDs): B@DNDs, P@DNDs, S@DNDs, N@DNDs, and SandN@DNDs There is a drastic decrease in highest occupied molecular orbital (HOMO) – lowest unoccupied molecular orbital (LUMO) energy gaps for nanoconjugates compared to DNDs alone. B@DNDs-NH2BzPc, SandN@DNDs-NH2BzPc, and P@DNDs-NH2BzPc showed superior photodynamic therapy (PDT) effects. DNDs-NH2BzPc also had a small HOMO-LUMO gap, but did not show improved PDT activity compared to the Pc alone, suggesting doping of DNDs is important. This study shows improved PDT effect on Michigan Cancer Foundation-7 breast cancer lines at 7.63%, 7.62% and 6.5% cell viability for P@DNDs-NH2BzPc, SandN@DNDs-NH2BzPc and B@DNDs-NH2BzPc, respectively.
- Full Text:
- Date Issued: 2020
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.
- Full Text:
- Date Issued: 2023
- 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.
- Full Text:
- Date Issued: 2023
Insights into the Dynamics and Binding of Two Polyprotein Substrate Cleavage Points in the Context of the SARS-CoV-2 Main and Papain-like Proteases
- Sanusi, Zainab K, Lobb, Kevin A
- Authors: Sanusi, Zainab K , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452773 , vital:75169 , xlink:href="https://doi.org/10.3390/molecules27238251"
- Description: It is well known that vital enzymes in the replication process of the coronavirus are the SARS-CoV-2 PLpro and SARS-CoV-2 3CLpro, both of which are important targets in the search for anti-coronavirus agents. These two enzymes are responsible for cleavage at various polyprotein sites in the SARS-CoV-2 lifecycle. Herein, the dynamics of the polyprotein cleavage sequences for the boundary between non-structural proteins Nsp1 and Nsp2 (CS1) and between Nsp2 and Nsp3 (CS2) in complex with both the papain-like protein PLpro and the main protease 3CLpro were explored using computational methods. The post dynamics analysis reveals that CS1 and CS2 both have greater stability when complexed with PLpro. Of these two, greater stability is observed for the CS1–PLpro complex, while destabilization resulting in loss of CS2 from the PLpro active site is observed for CS2-PLpro, suggesting the rate of exchange by the papain-like protease is faster for CS2 compared to CS1. On the other hand, the 3CLpro main protease also reveals stability for CS1 suggesting that the main protease could also play a potential role in the cleavage at point CS1. However, destabilization occurs early in the simulation for the complex CLpro–CS2 suggesting a poor interaction and non-plausible protease cleavage of the polyprotein at CS2 by the main protease. These findings could be used as a guide in the development and design of potent COVID-19 antiviral inhibitors that mimic the CS1 cleavage site.
- Full Text:
- Date Issued: 2022
- Authors: Sanusi, Zainab K , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452773 , vital:75169 , xlink:href="https://doi.org/10.3390/molecules27238251"
- Description: It is well known that vital enzymes in the replication process of the coronavirus are the SARS-CoV-2 PLpro and SARS-CoV-2 3CLpro, both of which are important targets in the search for anti-coronavirus agents. These two enzymes are responsible for cleavage at various polyprotein sites in the SARS-CoV-2 lifecycle. Herein, the dynamics of the polyprotein cleavage sequences for the boundary between non-structural proteins Nsp1 and Nsp2 (CS1) and between Nsp2 and Nsp3 (CS2) in complex with both the papain-like protein PLpro and the main protease 3CLpro were explored using computational methods. The post dynamics analysis reveals that CS1 and CS2 both have greater stability when complexed with PLpro. Of these two, greater stability is observed for the CS1–PLpro complex, while destabilization resulting in loss of CS2 from the PLpro active site is observed for CS2-PLpro, suggesting the rate of exchange by the papain-like protease is faster for CS2 compared to CS1. On the other hand, the 3CLpro main protease also reveals stability for CS1 suggesting that the main protease could also play a potential role in the cleavage at point CS1. However, destabilization occurs early in the simulation for the complex CLpro–CS2 suggesting a poor interaction and non-plausible protease cleavage of the polyprotein at CS2 by the main protease. These findings could be used as a guide in the development and design of potent COVID-19 antiviral inhibitors that mimic the CS1 cleavage site.
- Full Text:
- Date Issued: 2022
Synthesis and conformational studies of 5-bromo-1-[(N-substituted-carbamoyl) methyl]-7-azabenzimidazoles
- Oluwafemi, Kola A, Klein, Rosalyn, Lobb, Kevin A, Tshiwawa, Tendamudzimu, Isaacs, Michelle, Hoppe, Heinrich C, Kaye, Perry T
- Authors: Oluwafemi, Kola A , Klein, Rosalyn , Lobb, Kevin A , Tshiwawa, Tendamudzimu , Isaacs, Michelle , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452800 , vital:75171 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133811"
- Description: The Cs2CO3-catalysed condensation of 5-bromo-7-azabenzimidazole with a series of bromomethyl ketones has afforded a small library of ten, novel 5-bromo-1-[(N-substututed-carbamoyl)methyl]-7-azabenzimidazoles. Rotamerism in the products, as evidenced by the splitting of 1H- and 13C-NMR signals, is attributed to hindered internal rotation about the amide N-C(=O) bond, and has been explored using dynamic NMR (DNMR) analysis and computational methods at the GIAO B3LYP/6-311+G(2d,p) level of theory. Coalescence temperatures have been obtained for representative examples and rotational barriers determined experimentally and theoretically. A detailed theoretical analysis has been undertaken to explore conformations which may contribute to the relative populations of the s-cis and s-trans rotamers. The products have also been screened for cytotoxicity and activity against two parasitic protozoan strains (Plasmodium falciparum and Trypanosoma brucei).
- Full Text:
- Date Issued: 2022
- Authors: Oluwafemi, Kola A , Klein, Rosalyn , Lobb, Kevin A , Tshiwawa, Tendamudzimu , Isaacs, Michelle , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452800 , vital:75171 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133811"
- Description: The Cs2CO3-catalysed condensation of 5-bromo-7-azabenzimidazole with a series of bromomethyl ketones has afforded a small library of ten, novel 5-bromo-1-[(N-substututed-carbamoyl)methyl]-7-azabenzimidazoles. Rotamerism in the products, as evidenced by the splitting of 1H- and 13C-NMR signals, is attributed to hindered internal rotation about the amide N-C(=O) bond, and has been explored using dynamic NMR (DNMR) analysis and computational methods at the GIAO B3LYP/6-311+G(2d,p) level of theory. Coalescence temperatures have been obtained for representative examples and rotational barriers determined experimentally and theoretically. A detailed theoretical analysis has been undertaken to explore conformations which may contribute to the relative populations of the s-cis and s-trans rotamers. The products have also been screened for cytotoxicity and activity against two parasitic protozoan strains (Plasmodium falciparum and Trypanosoma brucei).
- Full Text:
- Date Issued: 2022
Synthesis, stereochemistry and in vitro STD NMR and in silico HIV-1 PR enzyme-binding potential of MBH-derived inhibitors
- Tukulula, Matshawandile, Olasupo, Idris A, Mugumbate, Grace C, Lobb, Kevin A, Klein, Rosalyn, Sayed, Yasien, Tshiwawa, Tendamudzimu, Kaye, Perry T
- Authors: Tukulula, Matshawandile , Olasupo, Idris A , Mugumbate, Grace C , Lobb, Kevin A , Klein, Rosalyn , Sayed, Yasien , Tshiwawa, Tendamudzimu , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452813 , vital:75172 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133716"
- Description: Aza-Michael reactions of a pyridine-3-carbaldehyde-derived Morita-Baylis-Hillman (MBH) adduct with various amines have afforded a series of 10 diastereomeric products, stereochemical analysis of which has been achieved using a combination of NMR (1D, 2D and NOESY) and computer modelling methods. Saturation Transfer Difference (STD) 1H NMR spectroscopy and in silico molecular docking studies have been used to explore the HIV-1 protease sub-type C enzyme binding potential of these compounds in five different HIV-1 PR enzyme receptors.
- Full Text:
- Date Issued: 2022
- Authors: Tukulula, Matshawandile , Olasupo, Idris A , Mugumbate, Grace C , Lobb, Kevin A , Klein, Rosalyn , Sayed, Yasien , Tshiwawa, Tendamudzimu , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452813 , vital:75172 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133716"
- Description: Aza-Michael reactions of a pyridine-3-carbaldehyde-derived Morita-Baylis-Hillman (MBH) adduct with various amines have afforded a series of 10 diastereomeric products, stereochemical analysis of which has been achieved using a combination of NMR (1D, 2D and NOESY) and computer modelling methods. Saturation Transfer Difference (STD) 1H NMR spectroscopy and in silico molecular docking studies have been used to explore the HIV-1 protease sub-type C enzyme binding potential of these compounds in five different HIV-1 PR enzyme receptors.
- Full Text:
- Date Issued: 2022
Inhibitory effects of selected cannabinoids against dipeptidyl peptidase IV, an enzyme linked to type 2 diabetes
- Mkabayi, Lithalethu, Viljoen, Zenobia, Krause, Rui W M, Lobb, Kevin A, Pletschke, Brett I, Frost, Carminita L
- Authors: Mkabayi, Lithalethu , Viljoen, Zenobia , Krause, Rui W M , Lobb, Kevin A , Pletschke, Brett I , Frost, Carminita L
- Date: 2024
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452760 , vital:75168 , xlink:href="https://doi.org/10.1016/j.heliyon.2023.e23289"
- Description: Ethnopharmacological relevance: In recent times the decriminalisation of cannabis globally has increased its use as an alternative medication. Where it has been used in modern medicinal practises since the 1800s, there is limited scientific investigation to understand the biological activities of this plant. Aim of the study: Dipeptidyl peptidase IV (DPP-IV) plays a key role in regulating glucose homeostasis, and inhibition of this enzyme has been used as a therapeutic approach to treat type 2 diabetes. However, some of the synthetic inhibitors for this enzyme available on the market may cause undesirable side effects. Therefore, it is important to identify new inhibitors of DPP-IV and to understand their interaction with this enzyme.
- Full Text:
- Date Issued: 2024
- Authors: Mkabayi, Lithalethu , Viljoen, Zenobia , Krause, Rui W M , Lobb, Kevin A , Pletschke, Brett I , Frost, Carminita L
- Date: 2024
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452760 , vital:75168 , xlink:href="https://doi.org/10.1016/j.heliyon.2023.e23289"
- Description: Ethnopharmacological relevance: In recent times the decriminalisation of cannabis globally has increased its use as an alternative medication. Where it has been used in modern medicinal practises since the 1800s, there is limited scientific investigation to understand the biological activities of this plant. Aim of the study: Dipeptidyl peptidase IV (DPP-IV) plays a key role in regulating glucose homeostasis, and inhibition of this enzyme has been used as a therapeutic approach to treat type 2 diabetes. However, some of the synthetic inhibitors for this enzyme available on the market may cause undesirable side effects. Therefore, it is important to identify new inhibitors of DPP-IV and to understand their interaction with this enzyme.
- Full Text:
- Date Issued: 2024
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.
- Full Text:
- Date Issued: 2021
- 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.
- Full Text:
- Date Issued: 2021
Inhibiting human dipeptidyl peptidase IV using cannabinoids and Leonotis leonurus extracts as a potential therapy for the management of diabetes
- Mkabayi, Lithalethu, Viljoen, Zenobia, Lobb, Kevin A, Pletschke, Brett I, Frost, Carminita L
- Authors: Mkabayi, Lithalethu , Viljoen, Zenobia , Lobb, Kevin A , Pletschke, Brett I , Frost, Carminita L
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452745 , vital:75167 , xlink:href="https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0043-1773924"
- Description: Diabetes is a chronic metabolic disorder that has been shown to affect a growing number of people worldwide. Controlling blood glucose levels is one of the possible strategies to treat type 2 diabetes mellitus (T2DM). It has been established that the inhibition of dipeptidyl peptidase IV (DPP-IV) prolongs the activity of incretin hormones, which serve as key stimulators of insulin secretion and regulation of blood glucose levels. Although several synthetic DPP-IV inhibitors are available, there is still a need for naturally sourced inhibitors that have fewer to no undesirable side effects. In this study, cannabinoids and Leonotis leonurus aqueous extracts were evaluated for their inhibitory effects against recombinant human DPP-IV. Their potential inhibition mechanism was explored using in vitro and in silico approaches. All tested cannabinoids and L. leonurus aqueous extracts showed significant inhibitory activity against DPP-IV. Phytochemical analysis of L. leonurus extract indicated the presence of diterpenoids and alkaloids, which might contribute to the inhibitory activity. In molecular docking studies, among different constituents known in L. leonurus, luteolin and marrubiin showed binding energy of -7.2 kcal/mol and cannabinoids (cannabidiol, cannabigerol, cannabinol and Δ9-tetrahydrocannabinol) showed binding energies ranging from -6.5 to -8.2 kcal/mol. Molecular dynamics revealed that all tested compounds formed stable complexes with the enzyme during 100 ns simulation, indicating that they are good ligands. This study provided preliminary evidence for the potential application of the selected cannabinoids and L. leonurus in maintaining glucose homeostasis, suggesting that they could be suitable therapeutic candidates for managing T2DM.
- Full Text:
- Date Issued: 2023
- Authors: Mkabayi, Lithalethu , Viljoen, Zenobia , Lobb, Kevin A , Pletschke, Brett I , Frost, Carminita L
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452745 , vital:75167 , xlink:href="https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0043-1773924"
- Description: Diabetes is a chronic metabolic disorder that has been shown to affect a growing number of people worldwide. Controlling blood glucose levels is one of the possible strategies to treat type 2 diabetes mellitus (T2DM). It has been established that the inhibition of dipeptidyl peptidase IV (DPP-IV) prolongs the activity of incretin hormones, which serve as key stimulators of insulin secretion and regulation of blood glucose levels. Although several synthetic DPP-IV inhibitors are available, there is still a need for naturally sourced inhibitors that have fewer to no undesirable side effects. In this study, cannabinoids and Leonotis leonurus aqueous extracts were evaluated for their inhibitory effects against recombinant human DPP-IV. Their potential inhibition mechanism was explored using in vitro and in silico approaches. All tested cannabinoids and L. leonurus aqueous extracts showed significant inhibitory activity against DPP-IV. Phytochemical analysis of L. leonurus extract indicated the presence of diterpenoids and alkaloids, which might contribute to the inhibitory activity. In molecular docking studies, among different constituents known in L. leonurus, luteolin and marrubiin showed binding energy of -7.2 kcal/mol and cannabinoids (cannabidiol, cannabigerol, cannabinol and Δ9-tetrahydrocannabinol) showed binding energies ranging from -6.5 to -8.2 kcal/mol. Molecular dynamics revealed that all tested compounds formed stable complexes with the enzyme during 100 ns simulation, indicating that they are good ligands. This study provided preliminary evidence for the potential application of the selected cannabinoids and L. leonurus in maintaining glucose homeostasis, suggesting that they could be suitable therapeutic candidates for managing T2DM.
- Full Text:
- Date Issued: 2023
Unveiling the reactivity of truxillic and truxinic acids (TXAs): deprotonation, anion center dot center dot center dot HO, cation center dot center dot center dot O and cation center dot center dot center dot pi interactions in TXA (0) center dot center dot center dot Y+ and TXA (0) center dot center dot center dot Z (-) complexes (Y= Li, Na, K; Z= F, Cl, Br)
- Isamura, Bienfait K, Patouossa, Issofa, Muya, Jules T, Lobb, Kevin A
- Authors: Isamura, Bienfait K , Patouossa, Issofa , Muya, Jules T , Lobb, Kevin A
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452827 , vital:75173 , xlink:href="https://link.springer.com/content/pdf/10.1007/s11224-022-01965-5.pdf"
- Description: Herein, we report a quantum chemistry investigation of the interaction between µ-truxinic acid, referred to as TXA0 , and Y+ (Y=Li, Na, K) and Z− (Z=F, Cl, Br) ions using M06-2X, B3LYP and 휔 B97XD functionals in conjunction with the 6–31+ +G(d,p), aug-cc-pVDZ(-X2C) and 6–311+ +G (d, p) basis sets. Our computations suggest that Y+ cations can bind to TXA0 through several combinations of cation…O and cation-π interactions, while Z− anions generally establish anion… H–O contacts. Predicted binding energies at the M06-2X/6–311+ +G(d,p) level range between−26.6 and−70.2 kcal/mol for cationic complexes and−20.4 and−62.3 kcal/mol for anionic ones. As such, TXA0 appears as an amphoteric molecule with a slight preference for electrophilic (cation... O) attacks. Furthermore, the most favourable binding site for cations allows for the formation of O…cation…O interactions where the cation is trapped between O37 and O38 atoms of TXA0 . Anions do not behave uniformly towards TXA0 : while the fuoride anion F− induces the deprotonation of TXA0 , Br− and Cl− do not. All of these structural insights are supported by topological calculations in the context of the quantum theory of atoms in molecules (QTAIM). Finally, SAPT0 analyses suggest that TXA0 …Y+ and TXA0 …Z− complexes are mainly stabilized by electrostatic and inductive efects, whose combined contributions account for more than 60 percent of the total interaction energy.
- Full Text:
- Date Issued: 2023
- Authors: Isamura, Bienfait K , Patouossa, Issofa , Muya, Jules T , Lobb, Kevin A
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452827 , vital:75173 , xlink:href="https://link.springer.com/content/pdf/10.1007/s11224-022-01965-5.pdf"
- Description: Herein, we report a quantum chemistry investigation of the interaction between µ-truxinic acid, referred to as TXA0 , and Y+ (Y=Li, Na, K) and Z− (Z=F, Cl, Br) ions using M06-2X, B3LYP and 휔 B97XD functionals in conjunction with the 6–31+ +G(d,p), aug-cc-pVDZ(-X2C) and 6–311+ +G (d, p) basis sets. Our computations suggest that Y+ cations can bind to TXA0 through several combinations of cation…O and cation-π interactions, while Z− anions generally establish anion… H–O contacts. Predicted binding energies at the M06-2X/6–311+ +G(d,p) level range between−26.6 and−70.2 kcal/mol for cationic complexes and−20.4 and−62.3 kcal/mol for anionic ones. As such, TXA0 appears as an amphoteric molecule with a slight preference for electrophilic (cation... O) attacks. Furthermore, the most favourable binding site for cations allows for the formation of O…cation…O interactions where the cation is trapped between O37 and O38 atoms of TXA0 . Anions do not behave uniformly towards TXA0 : while the fuoride anion F− induces the deprotonation of TXA0 , Br− and Cl− do not. All of these structural insights are supported by topological calculations in the context of the quantum theory of atoms in molecules (QTAIM). Finally, SAPT0 analyses suggest that TXA0 …Y+ and TXA0 …Z− complexes are mainly stabilized by electrostatic and inductive efects, whose combined contributions account for more than 60 percent of the total interaction energy.
- Full Text:
- Date Issued: 2023
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.
- Full Text:
- Date Issued: 2022
- 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.
- Full Text:
- Date Issued: 2022
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.
- Full Text:
- Date Issued: 2022
- 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.
- Full Text:
- Date Issued: 2022
Exploring DOXP-reductoisomerase binding limits using phosphonated N-aryl and N-heteroarylcarboxamides as DXR inhibitors
- Bodill, Taryn, Conibear, Anne C, Mutorwa, Marius K, Goble, Jessica L, Blatch, Gregory L, Lobb, Kevin A, Klein, Rosalyn, Kaye, Perry T
- Authors: Bodill, Taryn , Conibear, Anne C , Mutorwa, Marius K , Goble, Jessica L , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448912 , vital:74770 , xlink:href=""
- Description: DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand–receptor interactions.
- Full Text:
- Date Issued: 2013
- Authors: Bodill, Taryn , Conibear, Anne C , Mutorwa, Marius K , Goble, Jessica L , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448912 , vital:74770 , xlink:href=""
- Description: DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand–receptor interactions.
- Full Text:
- Date Issued: 2013
AMADAR: a python-based package for large scale prediction of Diels–Alder transition state geometries and IRC path analysis
- Isamura, Bienfait K, Lobb, Kevin A
- Authors: Isamura, Bienfait K , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453143 , vital:75226 , xlink:href="https://link.springer.com/article/10.1186/s13321-022-00618-3"
- Description: Predicting transition state geometries is one of the most challenging tasks in computational chemistry, which often requires expert-based knowledge and permanent human intervention. This short communication reports technical details and preliminary results of a python-based tool (AMADAR) designed to generate any Diels–Alder (DA) transition state geometry (TS) and analyze determined IRC paths in a (quasi-)automated fashion, given the product SMILES. Two modules of the package are devoted to performing, from IRC paths, reaction force analyses (RFA) and atomic (fragment) decompositions of the reaction force F and reaction force constant κ. The performance of the protocol has been assessed using a dataset of 2000 DA cycloadducts retrieved from the ZINC database. The sequential location of the corresponding TSs was achieved with a success rate of 95%. RFA plots confrmed the reaction force constant κ to be a good indicator of the (non)synchronicity of the associated DA reactions. Moreover, the atomic decomposition of κ allows for the rationalization of the (a)synchronicity of each DA reaction in terms of contributions stemming from pairs of interacting atoms. The source code of the AMADAR tool is available on GitHub [CMCDD/AMADAR(github. com)] and can be used directly with minor customizations, mostly regarding the local working environment of the user.
- Full Text:
- Date Issued: 2022
- Authors: Isamura, Bienfait K , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453143 , vital:75226 , xlink:href="https://link.springer.com/article/10.1186/s13321-022-00618-3"
- Description: Predicting transition state geometries is one of the most challenging tasks in computational chemistry, which often requires expert-based knowledge and permanent human intervention. This short communication reports technical details and preliminary results of a python-based tool (AMADAR) designed to generate any Diels–Alder (DA) transition state geometry (TS) and analyze determined IRC paths in a (quasi-)automated fashion, given the product SMILES. Two modules of the package are devoted to performing, from IRC paths, reaction force analyses (RFA) and atomic (fragment) decompositions of the reaction force F and reaction force constant κ. The performance of the protocol has been assessed using a dataset of 2000 DA cycloadducts retrieved from the ZINC database. The sequential location of the corresponding TSs was achieved with a success rate of 95%. RFA plots confrmed the reaction force constant κ to be a good indicator of the (non)synchronicity of the associated DA reactions. Moreover, the atomic decomposition of κ allows for the rationalization of the (a)synchronicity of each DA reaction in terms of contributions stemming from pairs of interacting atoms. The source code of the AMADAR tool is available on GitHub [CMCDD/AMADAR(github. com)] and can be used directly with minor customizations, mostly regarding the local working environment of the user.
- Full Text:
- Date Issued: 2022
Regioselectivity, chemical bonding and physical nature of the interaction between imidazole and XAHs (X= H, F, Cl, Br, CH3, and A= S, Se, Te)
- Isamura, Bienfait K, Lobb, Kevin A, Muya, Jules T
- Authors: Isamura, Bienfait K , Lobb, Kevin A , Muya, Jules T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453183 , vital:75229 , xlink:href="https://doi.org/10.1080/00268976.2022.2026511"
- Description: Theambidentreactivityofsmall-sizedXAHs(X=H,F,Cl,Br,CH3,andA=S,Se,Te)moleculestowardsthe imidazole molecule (IMZ) has been investigated using wave function (MP2) and Density Func-tional Theory (B3LYP, B3LYP-D3). Molecular electrostatic potentials (MEPs) and frontier molecularorbitals of monomers are computed to rationalise the regioselectivity of IMZ towards XAHs. Thechemical bonding of each complex is described in the framework of the quantum theory of atomsin molecules (QTAIM) and natural bond orbital (NBO) paradigms. The symmetry-adapted pertur-bation theory (SAPT) is employed to assess the physical nature of the interactions. Our findingssuggest that XAHs mainly bind to IMZ through H-bonding and chalcogen-bonding interactionsof weak to moderate strength, with binding energies ranging from−3.1 to−17.6 kcal/mol at theMP2/aug-cc-pVDZ(-PP) level. Topological QTAIM descriptors reveal all H-bonds between IMZ andXAHs to be purely noncovalent contacts, while chalcogen bonds of halogenated XAHs (X=F, Cl, Br) show a partial covalent character. SAPT2 calculations indicate that both H-bonded and chalcogen-bonded complexes are mainly stabilised by electrostatic interactions. Insights drawn from this studyare expected to constitute the bedrock for further investigations about noncovalent interactionbetween middle to big-sized chalcogen-containing molecules and imidazole derivatives.
- Full Text:
- Date Issued: 2022
- Authors: Isamura, Bienfait K , Lobb, Kevin A , Muya, Jules T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453183 , vital:75229 , xlink:href="https://doi.org/10.1080/00268976.2022.2026511"
- Description: Theambidentreactivityofsmall-sizedXAHs(X=H,F,Cl,Br,CH3,andA=S,Se,Te)moleculestowardsthe imidazole molecule (IMZ) has been investigated using wave function (MP2) and Density Func-tional Theory (B3LYP, B3LYP-D3). Molecular electrostatic potentials (MEPs) and frontier molecularorbitals of monomers are computed to rationalise the regioselectivity of IMZ towards XAHs. Thechemical bonding of each complex is described in the framework of the quantum theory of atomsin molecules (QTAIM) and natural bond orbital (NBO) paradigms. The symmetry-adapted pertur-bation theory (SAPT) is employed to assess the physical nature of the interactions. Our findingssuggest that XAHs mainly bind to IMZ through H-bonding and chalcogen-bonding interactionsof weak to moderate strength, with binding energies ranging from−3.1 to−17.6 kcal/mol at theMP2/aug-cc-pVDZ(-PP) level. Topological QTAIM descriptors reveal all H-bonds between IMZ andXAHs to be purely noncovalent contacts, while chalcogen bonds of halogenated XAHs (X=F, Cl, Br) show a partial covalent character. SAPT2 calculations indicate that both H-bonded and chalcogen-bonded complexes are mainly stabilised by electrostatic interactions. Insights drawn from this studyare expected to constitute the bedrock for further investigations about noncovalent interactionbetween middle to big-sized chalcogen-containing molecules and imidazole derivatives.
- Full Text:
- Date Issued: 2022
Synthesis of 2, 3-dihydroxy-3-(N-substituted carbamoyl) propylphosphonic acid derivatives as hybrid DOXP-fosmidomycin analogues
- Mutorwa, Marius K, Lobb, Kevin A, Klein, Rosalyn, Blatch, Gregory L, Kaye, Perry T
- Authors: Mutorwa, Marius K , Lobb, Kevin A , Klein, Rosalyn , Blatch, Gregory L , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453212 , vital:75231 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.132453"
- Description: A six-step synthetic pathway has been established to access a series of racemic 2,3-dihydroxy-3-(Nsubstituted carbamoyl)propylphosphonic acid derivatives, designed to contain structural features common to both the natural substrate 1-deoxy-D-xylulose 5-phosphate (DOXP) of the Plasmodium falciparum (Pf) DXR enzyme and its known inhibitor, fosmidomycin. Positive STD-NMR and in silico docking data obtained for some of the compounds indicate their capacity to bind to the analogous E.coli DXR enzyme.
- Full Text:
- Date Issued: 2022
- Authors: Mutorwa, Marius K , Lobb, Kevin A , Klein, Rosalyn , Blatch, Gregory L , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453212 , vital:75231 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.132453"
- Description: A six-step synthetic pathway has been established to access a series of racemic 2,3-dihydroxy-3-(Nsubstituted carbamoyl)propylphosphonic acid derivatives, designed to contain structural features common to both the natural substrate 1-deoxy-D-xylulose 5-phosphate (DOXP) of the Plasmodium falciparum (Pf) DXR enzyme and its known inhibitor, fosmidomycin. Positive STD-NMR and in silico docking data obtained for some of the compounds indicate their capacity to bind to the analogous E.coli DXR enzyme.
- Full Text:
- Date Issued: 2022
Introducing DerivatizeME and its Application in the Augmentation of a Natural Product Library
- Sigauke, Lester T, Taştan Bishop, Özlem, Lobb, Kevin A
- Authors: Sigauke, Lester T , Taştan Bishop, Özlem , Lobb, Kevin A
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451120 , vital:75020 , xlink:href="https://doi.org/10.1142/S2737416521500101"
- Description: The large chemical space universe can be traversed by screening libraries of compounds that possess novel medicinally relevant chemistries, properties and complexity criteria. These libraries can be populated with the use of exhaustive, de novo approaches or inspired, combinatorial approaches. By assuming that natural products within screening libraries may be classified as a source of feedstock for populating virtual libraries, they can act as scaffolds upon which exhaustive approaches may be used in exploring chemical space. In order to achieve this, we have built DerivatizeME as a tool that enumerates derivatives of query compounds in order to evaluate their relevance for further assessment and development. This technique was applied to natural products present in the South African natural compound database (SANCDB). By expanding the chemical space of SANCDB compounds through the generation of SANCDB derivatives, we were able to graduate some natural products that were in undesirable regions of medicinally relevant chemical space, to acceptable regions of this chemical space. These modified scaffolds are available for further development, testing and evaluation in a manner similar to natural product driven focused libraries. The natural product parent is used, through its derivatives, instead of being discarded from screening protocols. This approach has the potential to enhance the efficiency of the natural product library in providing successful hits, amplifying the potential that they possess to access both novel bioactives and privileged scaffolds which may have otherwise been overlooked.
- Full Text:
- Date Issued: 2021
- Authors: Sigauke, Lester T , Taştan Bishop, Özlem , Lobb, Kevin A
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451120 , vital:75020 , xlink:href="https://doi.org/10.1142/S2737416521500101"
- Description: The large chemical space universe can be traversed by screening libraries of compounds that possess novel medicinally relevant chemistries, properties and complexity criteria. These libraries can be populated with the use of exhaustive, de novo approaches or inspired, combinatorial approaches. By assuming that natural products within screening libraries may be classified as a source of feedstock for populating virtual libraries, they can act as scaffolds upon which exhaustive approaches may be used in exploring chemical space. In order to achieve this, we have built DerivatizeME as a tool that enumerates derivatives of query compounds in order to evaluate their relevance for further assessment and development. This technique was applied to natural products present in the South African natural compound database (SANCDB). By expanding the chemical space of SANCDB compounds through the generation of SANCDB derivatives, we were able to graduate some natural products that were in undesirable regions of medicinally relevant chemical space, to acceptable regions of this chemical space. These modified scaffolds are available for further development, testing and evaluation in a manner similar to natural product driven focused libraries. The natural product parent is used, through its derivatives, instead of being discarded from screening protocols. This approach has the potential to enhance the efficiency of the natural product library in providing successful hits, amplifying the potential that they possess to access both novel bioactives and privileged scaffolds which may have otherwise been overlooked.
- Full Text:
- Date Issued: 2021
Force Field Parameters for Fe2+ 4S2− 4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies
- Tendwa, Maureen B, Chebon-Bore, Lorna, Lobb, Kevin A, Musyoka, Thommas M, Taştan Bishop, Özlem
- Authors: Tendwa, Maureen B , Chebon-Bore, Lorna , Lobb, Kevin A , Musyoka, Thommas M , Taştan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451078 , vital:75016 , xlink:href="https://doi.org/10.3390/molecules26102929 "
- Description: The dimeric dihydropyrimidine dehydrogenase (DPD), metalloenzyme, an adjunct anti-cancer drug target, contains highly specialized 4 × Fe2+4S2−4 clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, the bulk of the administered 5-fluorouracil (5-FU) cancer drug is inactivated, while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combining molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe2+4S2−4 clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe2+ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe2+ centers, using the original Seminario method and the collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters, which accurately described the human DPD protein Fe2+4S2−4 cluster architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues.
- Full Text:
- Date Issued: 2021
- Authors: Tendwa, Maureen B , Chebon-Bore, Lorna , Lobb, Kevin A , Musyoka, Thommas M , Taştan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451078 , vital:75016 , xlink:href="https://doi.org/10.3390/molecules26102929 "
- Description: The dimeric dihydropyrimidine dehydrogenase (DPD), metalloenzyme, an adjunct anti-cancer drug target, contains highly specialized 4 × Fe2+4S2−4 clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, the bulk of the administered 5-fluorouracil (5-FU) cancer drug is inactivated, while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combining molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe2+4S2−4 clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe2+ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe2+ centers, using the original Seminario method and the collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters, which accurately described the human DPD protein Fe2+4S2−4 cluster architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues.
- Full Text:
- Date Issued: 2021
Ultrasound promoted synthesis, characterization and computational studies of some thiourea derivatives
- Odame, Felix, Hosten, Eric C, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451199 , vital:75028 , xlink:href="https://doi.org/10.1016/j.molstruc.2020.128302"
- Description: Synthesis of some thiourea derivatives have been achieved by using ultrasound, the compounds have been characterised using IR, NMR, GC-MS and elemental analysis. The single crystal X-ray structure of N-[(benzyloxy)methanethioyl]benzamide (IV), 1-benzoyl-3-(2-hydroxyethyl)thiourea (V) and 3-benzoyl-1-(1-benzylpiperidin-4-yl)thiourea (VI) has been presented and the bond lengths and bond angles contrasted with computed results. The HOMO and LUMO energy levels as well as the global chemical reactivity descriptors of the compounds have also been computed and discussed. Two comformers were obtained for compounds IV to VI in the molecular Electrostatic potential and the vibrational frequency computations and these have been discussed.
- Full Text:
- Date Issued: 2020
- Authors: Odame, Felix , Hosten, Eric C , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451199 , vital:75028 , xlink:href="https://doi.org/10.1016/j.molstruc.2020.128302"
- Description: Synthesis of some thiourea derivatives have been achieved by using ultrasound, the compounds have been characterised using IR, NMR, GC-MS and elemental analysis. The single crystal X-ray structure of N-[(benzyloxy)methanethioyl]benzamide (IV), 1-benzoyl-3-(2-hydroxyethyl)thiourea (V) and 3-benzoyl-1-(1-benzylpiperidin-4-yl)thiourea (VI) has been presented and the bond lengths and bond angles contrasted with computed results. The HOMO and LUMO energy levels as well as the global chemical reactivity descriptors of the compounds have also been computed and discussed. Two comformers were obtained for compounds IV to VI in the molecular Electrostatic potential and the vibrational frequency computations and these have been discussed.
- Full Text:
- Date Issued: 2020
Synthesis, characterization, computational studies and DPPH scavenging activity of some triazatetracyclic derivatives
- Odame, Felix, Hosten, Eric C, Betz, Richard, Krause, Jason, Frost, Carminita L, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Krause, Jason , Frost, Carminita L , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451186 , vital:75026 , xlink:href="https://doi.org/10.1007/s13738-021-02158-3"
- Description: Some dihydrobenzo[4,5]imidazo[1,2-c]quinazolines have been synthesized from aldehydes and ketones, using the ketones as both reagents and solvents and tetrahydrofuran (THF) as the solvent for the aldehydes, to yield the triazatetracyclics. The compounds have been characterized with spectroscopy and microanalysis. The crystal structures of 9,9-dimethyl-8,10,17- triazatetracyclo[8.7.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaene (I), 9-butyl-9-methyl-8,10,17-triazatetracyclo[8.7.0.02 , 7 .011,16]heptadeca-(17),2,4,6,11(16),12,14-heptaene (III) and 9-phenyl-8,10,17-triazatetracyclo[8.7.0 02 7.011,16] heptadeca-1(17),2,4,6,11(16),12,14-heptaene (VIII) have been discussed. The computed NMR, IR, molecular electrostatic potential and frontier molecular orbitals of compounds I, III and VIII have been discussed. The M06 functional gave most of its values closest to the experimental values for the bond lengths and bond angles of compounds I and III. For compound VIII, none of the functionals gave values for bond lengths and bond angles that were consistent with the experimental values, but M06 gave values closest to experimental values. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity of the triazatetracyclics showed that compound I exhibits signifcant DPPH scavenging activity with an IC50 of 56.18 µM compared to 2.37 µM for ascorbic acid.
- Full Text:
- Date Issued: 2021
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Krause, Jason , Frost, Carminita L , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451186 , vital:75026 , xlink:href="https://doi.org/10.1007/s13738-021-02158-3"
- Description: Some dihydrobenzo[4,5]imidazo[1,2-c]quinazolines have been synthesized from aldehydes and ketones, using the ketones as both reagents and solvents and tetrahydrofuran (THF) as the solvent for the aldehydes, to yield the triazatetracyclics. The compounds have been characterized with spectroscopy and microanalysis. The crystal structures of 9,9-dimethyl-8,10,17- triazatetracyclo[8.7.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaene (I), 9-butyl-9-methyl-8,10,17-triazatetracyclo[8.7.0.02 , 7 .011,16]heptadeca-(17),2,4,6,11(16),12,14-heptaene (III) and 9-phenyl-8,10,17-triazatetracyclo[8.7.0 02 7.011,16] heptadeca-1(17),2,4,6,11(16),12,14-heptaene (VIII) have been discussed. The computed NMR, IR, molecular electrostatic potential and frontier molecular orbitals of compounds I, III and VIII have been discussed. The M06 functional gave most of its values closest to the experimental values for the bond lengths and bond angles of compounds I and III. For compound VIII, none of the functionals gave values for bond lengths and bond angles that were consistent with the experimental values, but M06 gave values closest to experimental values. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity of the triazatetracyclics showed that compound I exhibits signifcant DPPH scavenging activity with an IC50 of 56.18 µM compared to 2.37 µM for ascorbic acid.
- Full Text:
- Date Issued: 2021