A multiscale ONIOM study of the buckminsterfullerene (C60) Diels–Alder reaction: from model design to reaction 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/10962/452517 , vital:75140 , xlink:href=" https://link.springer.com/article/10.1007/s00894-022-05319-0"
- Description: The hybrid ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) formalism is employed to investigate the Diels–Alder reaction of the buckminsterfullerene C60. Our computa-tions suggest that the ONIOM2(M06-2X/6-31G(d): SVWN/STO3G) mod-el, enclosing both the diene and the pyracyclene fragment of C60 in the higher-layer, provides a reasonable trade-of between accuracy and computational cost as it comes to predicting reaction energetics. Moreover, the frontier molecular orbital (FMO) theory and activation strain model (ASM) are jointly relied on to rationalize the efect of –OH and –CN substituents on the activation barrier of this reaction. Finally, reaction paths are scrutinized to get insight into the various forces un-derpinning the process of cycloadduct formation.
- 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/10962/452517 , vital:75140 , xlink:href=" https://link.springer.com/article/10.1007/s00894-022-05319-0"
- Description: The hybrid ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) formalism is employed to investigate the Diels–Alder reaction of the buckminsterfullerene C60. Our computa-tions suggest that the ONIOM2(M06-2X/6-31G(d): SVWN/STO3G) mod-el, enclosing both the diene and the pyracyclene fragment of C60 in the higher-layer, provides a reasonable trade-of between accuracy and computational cost as it comes to predicting reaction energetics. Moreover, the frontier molecular orbital (FMO) theory and activation strain model (ASM) are jointly relied on to rationalize the efect of –OH and –CN substituents on the activation barrier of this reaction. Finally, reaction paths are scrutinized to get insight into the various forces un-derpinning the process of cycloadduct formation.
- Full Text:
- Date Issued: 2022
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
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.
- Full Text:
- Date Issued: 2022
- 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.
- Full Text:
- Date Issued: 2022
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
Photo-and thermoresponsive N-salicylideneaniline derivatives: solid-state studies and structural aspects
- Hulushe, Siyabonga T, Malan, Frederick P, Hosten, Eric C, Lobb, Kevin A, Khanye, Setshaba D, Watkins, Gareth M
- Authors: Hulushe, Siyabonga T , Malan, Frederick P , Hosten, Eric C , Lobb, Kevin A , Khanye, Setshaba D , Watkins, Gareth M
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451137 , vital:75021 , xlink:href="https://pubs.rsc.org/en/content/articlehtml/2022/nj/d1nj03056f"
- Description: N-Salicylideneaniline (SA) and its derivatives are known to possess chromism upon exposure to external stimuli. Herein, we present mechanochemical synthesis of a series of photo-and thermoresponsive SAderivatives and report on solid-state stabilisation of their tautomeric forms either by change in temperature or by photoirradiation. The influence of UV light on proton transfer between the enol-imine (EI) and keto-amine (KA) forms was investigated at l1 = 254 and l2 = 365 nm. Differential scanning calorimetry (DSC) measurements provided extra information on the thermodynamic relationship between the prototropic tautomers, and their exposition to liquid nitrogen, combined with variable temperature single-crystal X-ray diffraction (VT-SCXRD) and spectroscopic data, ascertained structural reasons for the intrinsic thermo-optical properties of the compounds. A series of structural determinations between 150 and 300 K further shed light on the thermomechanical behaviour exhibited by the thermoresponsive compounds. By virtue of calorimetry we were able to demonstrate proton transfer via the intramolecular ON hydrogen bond over the temperature range 193–453 K. This present work demonstrates the importance of applying complementary analytical techniques and appropriate approaches for understanding the switching behaviour between the EI and KA forms. Furthermore, the assertion that it is predominantly the planarity (j o 251) that determines thermochromaticity is questioned.
- Full Text:
- Date Issued: 2022
- Authors: Hulushe, Siyabonga T , Malan, Frederick P , Hosten, Eric C , Lobb, Kevin A , Khanye, Setshaba D , Watkins, Gareth M
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451137 , vital:75021 , xlink:href="https://pubs.rsc.org/en/content/articlehtml/2022/nj/d1nj03056f"
- Description: N-Salicylideneaniline (SA) and its derivatives are known to possess chromism upon exposure to external stimuli. Herein, we present mechanochemical synthesis of a series of photo-and thermoresponsive SAderivatives and report on solid-state stabilisation of their tautomeric forms either by change in temperature or by photoirradiation. The influence of UV light on proton transfer between the enol-imine (EI) and keto-amine (KA) forms was investigated at l1 = 254 and l2 = 365 nm. Differential scanning calorimetry (DSC) measurements provided extra information on the thermodynamic relationship between the prototropic tautomers, and their exposition to liquid nitrogen, combined with variable temperature single-crystal X-ray diffraction (VT-SCXRD) and spectroscopic data, ascertained structural reasons for the intrinsic thermo-optical properties of the compounds. A series of structural determinations between 150 and 300 K further shed light on the thermomechanical behaviour exhibited by the thermoresponsive compounds. By virtue of calorimetry we were able to demonstrate proton transfer via the intramolecular ON hydrogen bond over the temperature range 193–453 K. This present work demonstrates the importance of applying complementary analytical techniques and appropriate approaches for understanding the switching behaviour between the EI and KA forms. Furthermore, the assertion that it is predominantly the planarity (j o 251) that determines thermochromaticity is questioned.
- 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
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
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 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
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
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
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