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
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
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
Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
- Diallo, Bakary N, Swart, Tarryn, Hoppe, Heinrich C, Tastan Bishop, Özlem, Lobb, Kevin A
- Authors: Diallo, Bakary N , Swart, Tarryn , Hoppe, Heinrich C , Tastan Bishop, Özlem , Lobb, Kevin A
- Date: 2021
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/177531 , vital:42830 , https://doi.org/10.1038/s41598-020-80722-2
- Description: Malaria elimination can benefit from time and cost-efficient approaches for antimalarials such as drug repurposing. In this work, 796 DrugBank compounds were screened against 36 Plasmodium falciparum targets using QuickVina-W. Hits were selected after rescoring using GRaph Interaction Matching (GRIM) and ligand efficiency metrics: surface efficiency index (SEI), binding efficiency index (BEI) and lipophilic efficiency (LipE). They were further evaluated in Molecular dynamics (MD). Twenty-five protein–ligand complexes were finally retained from the 28,656 (36×796) dockings.
- Full Text:
- Date Issued: 2021
- Authors: Diallo, Bakary N , Swart, Tarryn , Hoppe, Heinrich C , Tastan Bishop, Özlem , Lobb, Kevin A
- Date: 2021
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/177531 , vital:42830 , https://doi.org/10.1038/s41598-020-80722-2
- Description: Malaria elimination can benefit from time and cost-efficient approaches for antimalarials such as drug repurposing. In this work, 796 DrugBank compounds were screened against 36 Plasmodium falciparum targets using QuickVina-W. Hits were selected after rescoring using GRaph Interaction Matching (GRIM) and ligand efficiency metrics: surface efficiency index (SEI), binding efficiency index (BEI) and lipophilic efficiency (LipE). They were further evaluated in Molecular dynamics (MD). Twenty-five protein–ligand complexes were finally retained from the 28,656 (36×796) dockings.
- Full Text:
- Date Issued: 2021
SANCDB: an update on South African natural compounds and their readily available analogs
- Diallo, Bakary N, Glenister, Michael, Musyoka, Thommas M, Lobb, Kevin A, Taştan Bishop, Özlem
- Authors: Diallo, Bakary N , Glenister, Michael , Musyoka, Thommas M , Lobb, Kevin A , Taştan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451154 , vital:75023 , xlink:href="https://doi.org/10.1186/s13321-021-00514-2"
- 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: Diallo, Bakary N , Glenister, Michael , Musyoka, Thommas M , Lobb, Kevin A , Taştan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451154 , vital:75023 , xlink:href="https://doi.org/10.1186/s13321-021-00514-2"
- 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
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
A novel gold (I)-mediated intramolecular transamidation of benzoyl thiourea derivatives to form benzamides via dethiocyanation
- Odame, Felix, Woodcock, Guillaume, Hosten, Eric C, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Woodcock, Guillaume , 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/10962/446988 , vital:74575 , xlink:href="https://doi.org/10.1016/j.jorganchem.2020.121359"
- Description: A novel gold(I)-mediated intramolecular transamidation of thiourea derivatives to yield benzamides via dethiocyanation have been achieved by the reaction of 3-(1,3-benzothiazol-2-yl)-1-(benzoyl)thiourea derivatives in the presence of gold(I) precursors. The compounds have been characterized using IR, NMR, GC-MS and microanalysis. The single crystal XRD of 3-(1,3-benzothiazol-2-yl)-1-(3-bromobenzoyl)thiourea (5), 3-(1,3-benzothiazol-2-yl)-1-(3-methoxybenzoyl)thiourea (6), N-(benzothiazol-2-yl)benzamide (10), N-(benzothiazol-2-yl)-3-chlorobenzamide (11), N-(benzothiazol-2-yl)-4-nitrobenzamide (12), N-(benzothiazol-2-yl)-3-bromobenzamide (14) have been discussed. The novel transformation is thought to proceed by a gold(I)-mediated intramolecular transamidation reaction which releases thiocyanate to yield the benzamide. Density functional theory calculations have been used to support the proposed mechanism for this transformation.
- Full Text:
- Date Issued: 2020
- Authors: Odame, Felix , Woodcock, Guillaume , 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/10962/446988 , vital:74575 , xlink:href="https://doi.org/10.1016/j.jorganchem.2020.121359"
- Description: A novel gold(I)-mediated intramolecular transamidation of thiourea derivatives to yield benzamides via dethiocyanation have been achieved by the reaction of 3-(1,3-benzothiazol-2-yl)-1-(benzoyl)thiourea derivatives in the presence of gold(I) precursors. The compounds have been characterized using IR, NMR, GC-MS and microanalysis. The single crystal XRD of 3-(1,3-benzothiazol-2-yl)-1-(3-bromobenzoyl)thiourea (5), 3-(1,3-benzothiazol-2-yl)-1-(3-methoxybenzoyl)thiourea (6), N-(benzothiazol-2-yl)benzamide (10), N-(benzothiazol-2-yl)-3-chlorobenzamide (11), N-(benzothiazol-2-yl)-4-nitrobenzamide (12), N-(benzothiazol-2-yl)-3-bromobenzamide (14) have been discussed. The novel transformation is thought to proceed by a gold(I)-mediated intramolecular transamidation reaction which releases thiocyanate to yield the benzamide. Density functional theory calculations have been used to support the proposed mechanism for this transformation.
- Full Text:
- Date Issued: 2020
Rational design and regioselective synthesis of conformationally restricted furan-derived ligands as potential anti-malarial agents
- Mutorwa, Marius K, Nokalipa, Iviwe, Tanner, Delia C, Blatch, Gregory L, Lobb, Kevin A, Klein, Rosalyn, Kaye, Perry T
- Authors: Mutorwa, Marius K , Nokalipa, Iviwe , Tanner, Delia C , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447170 , vital:74589 , xlink:href="https://doi.org/10.24820/ark.5550190.p011.281"
- Description: Substituted 3-furanomethyl phosphate esters and their corresponding phosphoric acids have been prepared as conformationally restricted analogues of DOXP, the natural substrate for Plasmodium falciparum 1-deoxyD-xylulose-5-phosphate reductoisomerase (PfDXR), and fosmidomycin, an established inhibitor. Saturation Transfer Difference (STD) NMR analysis and in silico docking data suggest the potential of such compounds as PfDXR inhibitors.
- Full Text:
- Date Issued: 2020
- Authors: Mutorwa, Marius K , Nokalipa, Iviwe , Tanner, Delia C , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447170 , vital:74589 , xlink:href="https://doi.org/10.24820/ark.5550190.p011.281"
- Description: Substituted 3-furanomethyl phosphate esters and their corresponding phosphoric acids have been prepared as conformationally restricted analogues of DOXP, the natural substrate for Plasmodium falciparum 1-deoxyD-xylulose-5-phosphate reductoisomerase (PfDXR), and fosmidomycin, an established inhibitor. Saturation Transfer Difference (STD) NMR analysis and in silico docking data suggest the potential of such compounds as PfDXR inhibitors.
- Full Text:
- Date Issued: 2020
Synthesis and anti-parasitic activity of N-benzylated phosphoramidate Mg2+-chelating ligands
- Adeyemi, Christiana M, Hoppe, Heinrich C, Isaacs, Michelle, Mnkandhla, Dumisani, Lobb, Kevin A, Klein, Rosalyn, Kaye, Perry T
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Mnkandhla, Dumisani , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451171 , vital:75025 , xlink:href="https://doi.org/10.1016/j.bioorg.2020.104280"
- Description: A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg2+-chelating group, has been synthesised in five steps as analogues of fosmidomycin, a Plasmodium falciparum 1-deoxy-1-D-xylulose-5- phosphate reductoisomerase (PfDXR) inhibitor. The 3,4-dihydroxyphenyl group effectively replaces the Mg2+- chelating hydroxamic acid group in fosmidomycin. The compounds showed very encouraging anti-parasitic activity with IC50 values of 5.6–16.4 µM against Plasmodium falciparum parasites and IC50 values of 5.2 – 10.2 µM against Trypanosoma brucei brucei (T.b.brucei). Data obtained from in silico docking of the ligands in the PfDXR receptor cavity (3AU9)5 support their potential as PfDXR inhibitors.
- Full Text:
- Date Issued: 2020
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Mnkandhla, Dumisani , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451171 , vital:75025 , xlink:href="https://doi.org/10.1016/j.bioorg.2020.104280"
- Description: A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg2+-chelating group, has been synthesised in five steps as analogues of fosmidomycin, a Plasmodium falciparum 1-deoxy-1-D-xylulose-5- phosphate reductoisomerase (PfDXR) inhibitor. The 3,4-dihydroxyphenyl group effectively replaces the Mg2+- chelating hydroxamic acid group in fosmidomycin. The compounds showed very encouraging anti-parasitic activity with IC50 values of 5.6–16.4 µM against Plasmodium falciparum parasites and IC50 values of 5.2 – 10.2 µM against Trypanosoma brucei brucei (T.b.brucei). Data obtained from in silico docking of the ligands in the PfDXR receptor cavity (3AU9)5 support their potential as PfDXR inhibitors.
- Full Text:
- Date Issued: 2020
Synthesis, characterization and biological activity of some Dithiourea Derivatives:
- Odame, Felix, Hosten, Eric C, Krause, Jason, Isaacs, Michelle, Hoppe, Heinrich C, Khanye, Setshaba D, Sayed, Yasien, Frost, Carminita L, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Krause, Jason , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Sayed, Yasien , Frost, Carminita L , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163046 , vital:41007 , DOI: 10.17344/acsi.2019.5689
- Description: Novel dithiourea derivatives have been designed as HIV-1 protease inhibitors using Autodock 4.2, synthesized and characterized by spectroscopic methods and microanalysis.
- Full Text:
- Date Issued: 2020
- Authors: Odame, Felix , Hosten, Eric C , Krause, Jason , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Sayed, Yasien , Frost, Carminita L , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163046 , vital:41007 , DOI: 10.17344/acsi.2019.5689
- Description: Novel dithiourea derivatives have been designed as HIV-1 protease inhibitors using Autodock 4.2, synthesized and characterized by spectroscopic methods and microanalysis.
- Full Text:
- Date Issued: 2020
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
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
Characterization and computational studies of 2-(benzamido) thiazol-5-yl benzoate
- Odame, Felix, Hosten, Eric C, Betz, Richard, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447003 , vital:74576 , xlink:href="https://doi.org/10.1134/S0022476619010190"
- Description: Thiazoles have shown a broad range of biological activities and are found in many potent biologically active molecules such as Sulfathiazol (antimicrobial drug), Ritonavir (antiretroviral drug), Abafungin (antifungal drug), and Tiazofurin (antineoplastic drug) [1]. They have exhibited some degree of plant growth regulatory and antifungal activities [2], whilst some thiazoles have shown anti-infective [3] as well as antibacterial activities [4]. The regio-controlled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl-2-bromo-5-chloro-4-thiazolecarboxylates using sequential palladium-catalyzed coupling reactions has been reported [5]. An efficient general method for the preparation of 2,4-di- and trisubsituted thiazoles is via P–TsOH. H2O-Catalyzed cyclization of trisubstituted propargylic alcohols with thioamides has been accomplished with moderate to excellent product yields under mild and standard conditions [6]. In the presence of triethylamine, (Z)-(2-acetoxyl-1-alkenyl) phenyl-λ3 iodanes reacts with thioureas or thioamides in methanol to afford 2,4- disubstituted thiazoles in good yields. The reaction is thought to proceed by the generation of highly reactive α-λ3 iodanyl ketones through ester exchange of the β-acetoxy group with liberation of methyl acetate, followed by nucleophilic substitutions with thioureas or thioamides [7].
- Full Text:
- Date Issued: 2019
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447003 , vital:74576 , xlink:href="https://doi.org/10.1134/S0022476619010190"
- Description: Thiazoles have shown a broad range of biological activities and are found in many potent biologically active molecules such as Sulfathiazol (antimicrobial drug), Ritonavir (antiretroviral drug), Abafungin (antifungal drug), and Tiazofurin (antineoplastic drug) [1]. They have exhibited some degree of plant growth regulatory and antifungal activities [2], whilst some thiazoles have shown anti-infective [3] as well as antibacterial activities [4]. The regio-controlled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl-2-bromo-5-chloro-4-thiazolecarboxylates using sequential palladium-catalyzed coupling reactions has been reported [5]. An efficient general method for the preparation of 2,4-di- and trisubsituted thiazoles is via P–TsOH. H2O-Catalyzed cyclization of trisubstituted propargylic alcohols with thioamides has been accomplished with moderate to excellent product yields under mild and standard conditions [6]. In the presence of triethylamine, (Z)-(2-acetoxyl-1-alkenyl) phenyl-λ3 iodanes reacts with thioureas or thioamides in methanol to afford 2,4- disubstituted thiazoles in good yields. The reaction is thought to proceed by the generation of highly reactive α-λ3 iodanyl ketones through ester exchange of the β-acetoxy group with liberation of methyl acetate, followed by nucleophilic substitutions with thioureas or thioamides [7].
- Full Text:
- Date Issued: 2019
Establishing computational approaches towards identifying malarial allosteric modulators: a case study of plasmodium falciparum hsp70s
- Amusengeri, Arnold, Astl, Lindy, Lobb, Kevin A, Verkhivker, Gennady M, Tastan Bishop, Özlem
- Authors: Amusengeri, Arnold , Astl, Lindy , Lobb, Kevin A , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163000 , vital:41003 , https://doi.org/10.3390/ijms20225574
- Description: Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control mechanisms. Yet, studies on designing allosteric modulators against them are limited. Here, we identified allosteric modulators (SANC190 and SANC651) against P. falciparum Hsp70-1 and Hsp70-x, affecting the conformational dynamics of the proteins, delicately balanced by the endogenous ligands. Previously, we established a pipeline to identify allosteric sites and modulators. This study also further investigated alternative approaches to speed up the process by comparing all atom molecular dynamics simulations and dynamic residue network analysis with the coarse-grained (CG) versions of the calculations. Betweenness centrality (BC) profiles for PfHsp70-1 and PfHsp70-x derived from CG simulations not only revealed similar trends but also pointed to the same functional regions and specific residues corresponding to BC profile peaks.
- Full Text:
- Date Issued: 2019
- Authors: Amusengeri, Arnold , Astl, Lindy , Lobb, Kevin A , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163000 , vital:41003 , https://doi.org/10.3390/ijms20225574
- Description: Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control mechanisms. Yet, studies on designing allosteric modulators against them are limited. Here, we identified allosteric modulators (SANC190 and SANC651) against P. falciparum Hsp70-1 and Hsp70-x, affecting the conformational dynamics of the proteins, delicately balanced by the endogenous ligands. Previously, we established a pipeline to identify allosteric sites and modulators. This study also further investigated alternative approaches to speed up the process by comparing all atom molecular dynamics simulations and dynamic residue network analysis with the coarse-grained (CG) versions of the calculations. Betweenness centrality (BC) profiles for PfHsp70-1 and PfHsp70-x derived from CG simulations not only revealed similar trends but also pointed to the same functional regions and specific residues corresponding to BC profile peaks.
- Full Text:
- Date Issued: 2019
High throughput screening, docking, and molecular dynamics studies to identify potential inhibitors of human calcium/calmodulin-dependent protein kinase IV
- Beg, Anam, Khan, Faez I, Lobb, Kevin A, Islam, Asimul, Ahmad, Faizan, Hassan, M Imtaiyaz
- Authors: Beg, Anam , Khan, Faez I , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/${Handle} , vital:74587 , xlink:href="https://doi.org/10.1080/07391102.2018.1479310"
- Description: Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is associated with many diseases including cancer and neurodegenerative disorders and thus being considered as a potential drug target. Here, we have employed the knowledge of three-dimensional structure of CAMKIV to identify new inhibitors for possible therapeutic intervention. We have employed virtual high throughput screening of 12,500 natural compounds of Zinc database to screen the best possible inhibitors of CAMKIV. Subsequently, 40 compounds which showed significant docking scores (−11.6 to −10.0 kcal/mol) were selected and further filtered through Lipinski rule and drug likeness parameter to get best inhibitors of CAMKIV. Docking results are indicating that ligands are binding to the hydrophobic cavity of the kinase domain of CAMKIV and forming a significant number of non-covalent interactions. Four compounds, ZINC02098378, ZINC12866674, ZINC04293413, and ZINC13403020, showing excellent binding affinity and drug likeness were subjected to molecular dynamics simulation to evaluate their mechanism of interaction and stability of protein-ligand complex. Our observations clearly suggesting that these selected ligands may be further employed for therapeutic intervention to address CAMKIV associated diseases.
- Full Text:
- Date Issued: 2019
- Authors: Beg, Anam , Khan, Faez I , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/${Handle} , vital:74587 , xlink:href="https://doi.org/10.1080/07391102.2018.1479310"
- Description: Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is associated with many diseases including cancer and neurodegenerative disorders and thus being considered as a potential drug target. Here, we have employed the knowledge of three-dimensional structure of CAMKIV to identify new inhibitors for possible therapeutic intervention. We have employed virtual high throughput screening of 12,500 natural compounds of Zinc database to screen the best possible inhibitors of CAMKIV. Subsequently, 40 compounds which showed significant docking scores (−11.6 to −10.0 kcal/mol) were selected and further filtered through Lipinski rule and drug likeness parameter to get best inhibitors of CAMKIV. Docking results are indicating that ligands are binding to the hydrophobic cavity of the kinase domain of CAMKIV and forming a significant number of non-covalent interactions. Four compounds, ZINC02098378, ZINC12866674, ZINC04293413, and ZINC13403020, showing excellent binding affinity and drug likeness were subjected to molecular dynamics simulation to evaluate their mechanism of interaction and stability of protein-ligand complex. Our observations clearly suggesting that these selected ligands may be further employed for therapeutic intervention to address CAMKIV associated diseases.
- Full Text:
- Date Issued: 2019
Identification and evaluation of bioactive natural products as potential inhibitors of human microtubule affinity-regulating kinase 4 (MARK4)
- Mohammad, Taj, Khan, Faez I, Lobb, Kevin A, Islam, Asimul, Ahmad, Faizan, Hassan, M Imtaiyaz
- Authors: Mohammad, Taj , Khan, Faez I , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447159 , vital:74588 , xlink:href="https://doi.org/10.1080/07391102.2018.1468282"
- Description: Microtubule affinity-regulating kinase 4 (MARK4) has recently been identified as a potential drug target for several complex diseases including cancer, diabetes and neurodegenerative disorders. Inhibition of MARK4 activity is an appealing therapeutic option to treat such diseases. Here, we have performed structure-based virtual high-throughput screening of 100,000 naturally occurring compounds from ZINC database against MARK4 to find its potential inhibitors. The resulted hits were selected, based on the binding affinities, docking scores and selectivity. Further, binding energy calculation, Lipinski filtration and ADMET prediction were carried out to find safe and better hits against MARK4. Best 10 compounds bearing high specificity and binding efficiency were selected, and their binding pattern to MARK4 was analyzed in detail. Finally, 100 ns molecular dynamics simulation was performed to evaluate; the dynamics stability of MARK4-compound complex. In conclusion, these selected natural compounds from ZINC database might be potential leads against MARK4, and can further be exploited in drug design and development for associated diseases.
- Full Text:
- Date Issued: 2019
- Authors: Mohammad, Taj , Khan, Faez I , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447159 , vital:74588 , xlink:href="https://doi.org/10.1080/07391102.2018.1468282"
- Description: Microtubule affinity-regulating kinase 4 (MARK4) has recently been identified as a potential drug target for several complex diseases including cancer, diabetes and neurodegenerative disorders. Inhibition of MARK4 activity is an appealing therapeutic option to treat such diseases. Here, we have performed structure-based virtual high-throughput screening of 100,000 naturally occurring compounds from ZINC database against MARK4 to find its potential inhibitors. The resulted hits were selected, based on the binding affinities, docking scores and selectivity. Further, binding energy calculation, Lipinski filtration and ADMET prediction were carried out to find safe and better hits against MARK4. Best 10 compounds bearing high specificity and binding efficiency were selected, and their binding pattern to MARK4 was analyzed in detail. Finally, 100 ns molecular dynamics simulation was performed to evaluate; the dynamics stability of MARK4-compound complex. In conclusion, these selected natural compounds from ZINC database might be potential leads against MARK4, and can further be exploited in drug design and development for associated diseases.
- Full Text:
- Date Issued: 2019
In silico study of Plasmodium 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) for identification of novel inhibitors from SANCDB:
- Diallo, Bakary N, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162687 , vital:40973 , https://doi.org/10.21955/aasopenres.1114960.1
- Description: In this study, we intended to find potential 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) inhibitors as antimalarial drugs from the South African National Compound Database (SANCDB; https://sancdb.rubi.ru.ac.za) using computational tools.
- Full Text:
- Date Issued: 2019
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162687 , vital:40973 , https://doi.org/10.21955/aasopenres.1114960.1
- Description: In this study, we intended to find potential 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) inhibitors as antimalarial drugs from the South African National Compound Database (SANCDB; https://sancdb.rubi.ru.ac.za) using computational tools.
- Full Text:
- Date Issued: 2019
Novel potential antimalarials through drug repurposing and multitargeting: a Computational Approach
- Diallo, Bakary N, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162676 , vital:40972 , https://doi.org/10.21955/aasopenres.1114955.1
- Description: This study aims to identify potential antimalarials from Food and Drug Administration (FDA) approved drugs.
- Full Text:
- Date Issued: 2019
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162676 , vital:40972 , https://doi.org/10.21955/aasopenres.1114955.1
- Description: This study aims to identify potential antimalarials from Food and Drug Administration (FDA) approved drugs.
- Full Text:
- Date Issued: 2019
Synthesis of N-Substituted phosphoramidic acid esters as “reverse” fosmidomycin analogues
- Adeyemi, Christiana M, Hoppe, Heinrich C, Isaacs, Michelle, Klein, Rosalyn, Lobb, Kevin A, Kaye, Perry T
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Klein, Rosalyn , Lobb, Kevin A , Kaye, Perry T
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/443238 , vital:74101 , https://doi.org/10.1016/j.tet.2019.02.003
- Description: An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”.
- Full Text:
- Date Issued: 2019
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Klein, Rosalyn , Lobb, Kevin A , Kaye, Perry T
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/443238 , vital:74101 , https://doi.org/10.1016/j.tet.2019.02.003
- Description: An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”.
- Full Text:
- Date Issued: 2019
Synthesis of N-Substituted phosphoramidic acid esters as “reverse” fosmidomycin analogues
- Adeyemi, Christiana M, Hoppe, Heinrich C, Isaacs, Michelle, Klein, Rosalyn, Lobb, Kevin A, Kaye, Perry T
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Klein, Rosalyn , Lobb, Kevin A , Kaye, Perry T
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447196 , vital:74591 , xlink:href="https://doi.org/10.1016/j.tet.2019.02.003"
- Description: An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”.
- Full Text:
- Date Issued: 2019
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Klein, Rosalyn , Lobb, Kevin A , Kaye, Perry T
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447196 , vital:74591 , xlink:href="https://doi.org/10.1016/j.tet.2019.02.003"
- Description: An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”.
- Full Text:
- Date Issued: 2019