Activity of diverse chalcones against several targets: statistical analysis of a high-throughput virtual screen of a custom chalcone library
- Authors: Sarron, Arthur F D
- Date: 2020
- Subjects: Acetophenone , Benzaldehyde , Ketones , Pyruvate kinase , Drug development , Aromatic compounds , Heat shock proteins
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/116028 , vital:34291
- Description: Chalcone family molecules are well known to have therapeutic proprieties (anti-inflammatory, anti-microbial or anti-cancer, etc). However the mechanism of action in some cases is not well known. A virtual library of this family of compounds was constructed using custom scripts, based on the aldol condensation, and this library was modified further to analogues by expansion of the α,β-unsaturated ketone linker. Acetophenone and benzaldehyde derivatives which are available and purchasable were used as a base to design the chalcone virtual library. 8063 chalcones were constructed and geometrically optimized with Gaussian 09. Their physicochemical characteristics linked to the Lipinski rules were analyzed with Knime and CDK. The entire library was after docked against several targets including HIV-1 integrase, MRSA pyruvate kinase, HSP90, COX-1, COX-2, ALR2, MAOA, MAOB, acetylcholinesterase, butyrylcholinesterase and PLA2. With the exception of MAOA, which does not have a crystal structure ligand, all dockings were validated by redocking the original ligand provided by the literature. These targets are known in the literature to be inhibited by chalcone-derivatives. However, specificity of the particular known chalcone inhibitors to the particular targets is not known. To this end the performance of the generated chalcone library against the list of targets was of interest. The binding energy of ligand-protein complexes was generally good across the library. Statistical analysis including principal component analysis and hierarchical clustering analysis were made in order to investigate for any physical/chemical characteristics which might explain what chalcone features affect the binding energy of the ligand-protein complexes. The spherical polar coordinates defining the orientation of the binding poses were also calculated and used in the statistical analysis. The statistical analysis has allowed us to hypothesize the importance of these radial distances and the polar angles of key atoms in the chalcones in binding to the pyruvate kinase crystal structure. This was validated by the docking of another small library of compound models in which the α,β-unsaturated ketone chain of the chalcone was replaced by incrementally longer conjugated chains. Further studies on the chalcones themselves reveal rotameric systems in both cis and trans-configurations (which may impact binding), and also studied was the effect of Topliss-based modification and its impact of binding to HSP90. Molecular dynamics confirmed good binding of identified chalcone hits.
- Full Text:
- Authors: Sarron, Arthur F D
- Date: 2020
- Subjects: Acetophenone , Benzaldehyde , Ketones , Pyruvate kinase , Drug development , Aromatic compounds , Heat shock proteins
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/116028 , vital:34291
- Description: Chalcone family molecules are well known to have therapeutic proprieties (anti-inflammatory, anti-microbial or anti-cancer, etc). However the mechanism of action in some cases is not well known. A virtual library of this family of compounds was constructed using custom scripts, based on the aldol condensation, and this library was modified further to analogues by expansion of the α,β-unsaturated ketone linker. Acetophenone and benzaldehyde derivatives which are available and purchasable were used as a base to design the chalcone virtual library. 8063 chalcones were constructed and geometrically optimized with Gaussian 09. Their physicochemical characteristics linked to the Lipinski rules were analyzed with Knime and CDK. The entire library was after docked against several targets including HIV-1 integrase, MRSA pyruvate kinase, HSP90, COX-1, COX-2, ALR2, MAOA, MAOB, acetylcholinesterase, butyrylcholinesterase and PLA2. With the exception of MAOA, which does not have a crystal structure ligand, all dockings were validated by redocking the original ligand provided by the literature. These targets are known in the literature to be inhibited by chalcone-derivatives. However, specificity of the particular known chalcone inhibitors to the particular targets is not known. To this end the performance of the generated chalcone library against the list of targets was of interest. The binding energy of ligand-protein complexes was generally good across the library. Statistical analysis including principal component analysis and hierarchical clustering analysis were made in order to investigate for any physical/chemical characteristics which might explain what chalcone features affect the binding energy of the ligand-protein complexes. The spherical polar coordinates defining the orientation of the binding poses were also calculated and used in the statistical analysis. The statistical analysis has allowed us to hypothesize the importance of these radial distances and the polar angles of key atoms in the chalcones in binding to the pyruvate kinase crystal structure. This was validated by the docking of another small library of compound models in which the α,β-unsaturated ketone chain of the chalcone was replaced by incrementally longer conjugated chains. Further studies on the chalcones themselves reveal rotameric systems in both cis and trans-configurations (which may impact binding), and also studied was the effect of Topliss-based modification and its impact of binding to HSP90. Molecular dynamics confirmed good binding of identified chalcone hits.
- Full Text:
An intervention on supporting teachers’ understanding of and mediation of learning of stoichiometry in selected schools in the Zambezi Region
- Authors: Denuga, Desalu Dedayo
- Date: 2020
- Subjects: Stoichiometry -- Study and teaching (Secondary) -- Namibia , Chemistry -- Study and teaching (Secondary) -- Namibia , Participant observation -- Namibia , Constructivism (Education) -- Namibia , Pedagogical content knowledge -- Namibia , Continuing education -- Namibia , Teachers -- In-service training -- Namibia
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/103855 , vital:32315
- Description: This study has been triggered by the results on stoichiometry questions in the Directorate of Namibian Examination Assessment’s (DNEA) scripts. As highlighted in the examiners’ reports, stoichiometry is an ongoing annual problem for most students in Namibia. It is against this background that I decided to explore the possibility of an intervention in the form of continuing professional development (CPD) and collaboration workshops to improve the understanding and the mediation of learning of stoichiometry by Physical Science teachers in the Zambezi Region of Namibia. The study was underpinned by an interpretive paradigm and within this paradigm a qualitative case study approach was adopted. Since this study was in a form of an intervention, a participatory action research (PAR) approach was employed within the community of practice (CoP). I used document analysis, workshop discussions, observations and videotaped lessons, interviews (semi-structured and stimulated recall interviews) and reflections to gather data. The study was carried out at three senior secondary schools and six Physical Science teachers were involved. The study drew on the theory of constructivism as a theoretical framework, namely, Piaget’s cognitive constructivism and Vygotsky‘s social constructivism as well as Shulman’s pedagogical content knowledge (PCK). Within PCK, Mavhunga and Rollnick’s Topic Specific Pedagogical Content Knowledge (TSPCK) was used as an analytical lens (Appendix L) in this study. The findings reveal that the use of a diagnostic test on learners made the Physical Science teachers aware of the learners’ challenges and what was difficult for them to understand in stoichiometry. It also helped in their understanding of the use of prior knowledge, one of the tenets of TSPCK, to access what learners knew about stoichiometry. Further findings of the study illuminate that the Physical Science teachers’ subject matter knowledge, pedagogical content knowledge and skills had shifted as a result of their participation in the intervention workshops. The findings of this study indicate that the CoP members acquired the professional transformations which were important breakthroughs in their careers. The study thus recommends that teachers should develop effective teacher professional development activities such as study teams, exemplary lessons, cluster teaching, and peer coaching where teachers are expected to examine their assumptions and practices continuously. The implication of my study is that the developed exemplary lesson during the intervention workshops by CoP members could be useful to other Physical Science teachers in the teaching of stoichiometry in all the schools in the Zambezi Region.
- Full Text:
- Authors: Denuga, Desalu Dedayo
- Date: 2020
- Subjects: Stoichiometry -- Study and teaching (Secondary) -- Namibia , Chemistry -- Study and teaching (Secondary) -- Namibia , Participant observation -- Namibia , Constructivism (Education) -- Namibia , Pedagogical content knowledge -- Namibia , Continuing education -- Namibia , Teachers -- In-service training -- Namibia
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/103855 , vital:32315
- Description: This study has been triggered by the results on stoichiometry questions in the Directorate of Namibian Examination Assessment’s (DNEA) scripts. As highlighted in the examiners’ reports, stoichiometry is an ongoing annual problem for most students in Namibia. It is against this background that I decided to explore the possibility of an intervention in the form of continuing professional development (CPD) and collaboration workshops to improve the understanding and the mediation of learning of stoichiometry by Physical Science teachers in the Zambezi Region of Namibia. The study was underpinned by an interpretive paradigm and within this paradigm a qualitative case study approach was adopted. Since this study was in a form of an intervention, a participatory action research (PAR) approach was employed within the community of practice (CoP). I used document analysis, workshop discussions, observations and videotaped lessons, interviews (semi-structured and stimulated recall interviews) and reflections to gather data. The study was carried out at three senior secondary schools and six Physical Science teachers were involved. The study drew on the theory of constructivism as a theoretical framework, namely, Piaget’s cognitive constructivism and Vygotsky‘s social constructivism as well as Shulman’s pedagogical content knowledge (PCK). Within PCK, Mavhunga and Rollnick’s Topic Specific Pedagogical Content Knowledge (TSPCK) was used as an analytical lens (Appendix L) in this study. The findings reveal that the use of a diagnostic test on learners made the Physical Science teachers aware of the learners’ challenges and what was difficult for them to understand in stoichiometry. It also helped in their understanding of the use of prior knowledge, one of the tenets of TSPCK, to access what learners knew about stoichiometry. Further findings of the study illuminate that the Physical Science teachers’ subject matter knowledge, pedagogical content knowledge and skills had shifted as a result of their participation in the intervention workshops. The findings of this study indicate that the CoP members acquired the professional transformations which were important breakthroughs in their careers. The study thus recommends that teachers should develop effective teacher professional development activities such as study teams, exemplary lessons, cluster teaching, and peer coaching where teachers are expected to examine their assumptions and practices continuously. The implication of my study is that the developed exemplary lesson during the intervention workshops by CoP members could be useful to other Physical Science teachers in the teaching of stoichiometry in all the schools in the Zambezi Region.
- Full Text:
Synthesis, characterisation and electrocatalytic behaviour of three series of Metal Organic Frameworks
- Authors: Murinzi, Tafadzwa Wendy
- Date: 2020
- Subjects: Electrochemistry , Metal-organic frameworks , Polyoxometalates , Fourier transform infrared spectroscopy , Electrocatalysis , Cysteine
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/167598 , vital:41495
- Description: Metal organic frameworks (MOFs) have received a lot of attention over the past few years due to their vast range of interesting properties and applications, such as catalysis, environmental sensing and storage. This wide range of potential applications is afforded by careful selection and manipulation of the components chosen in assembling of MOFs. In this study, three series of MOFs were synthesized from Co(II), Cu(II) and Mo(VI) polyoxometallates with either 1,3,5-benzenetricarboxylic acid, 1,2,4,5-benzenetetracarboxylic acid or 2,6- pyridinedicarboxylic acid as the ligands. In series 1, the common 1,3,5- benzenetricarboxylic acid MOF, HKUST-1, and POM modified HKUST-1 compounds involving encapsulation and encorporation of the POM were utilised. In series 2, flexible cobalt(II) benzenepolycarboxylate MOFs which investigated the effect of varying the degree of carboxylate substituent were utilised. In series 3, flexibly reduced heterocyclic polycarboxylate MOFs using 2,6-pyridine dicarboxylate were utilised. Solvothermal and slow evaporation synthesis conditions were employed. Where single crystals of good quality were produced, single crystal X-ray diffraction (SC-XRD) was employed for structural elucidation. In the absence of such crystals, a combination of elemental analysis, inductively coupled plasma optical emission spectrometry (ICP-OES) and powder X-ray diffraction (PXRD) was used. Characterization of the MOFs was done by Fourier transform infrared spectrometry (FTIR) and thermal methods, namely thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The electrocatalytic potential of the compounds in the oxidation of L-cysteine was then investigated using a variety of techniques. Cyclic voltammetry was used for L-cysteine detection whilst chronoamperometry and differential pulse voltammetry were used to determine the nanoprobes’ sensitivity, rate constants and detection limits. Electrochemical impedence spectroscopy was used to investigate the charge transfer resistance (RCT) and electron transfer kinetics. Of the three, series 3 gave the best signals and sensitivities for electrocatalysis of L-cysteine followed by series 2 and lastly series 1. Series 2 showed the highest stability and series 1 required the least overpotential. The results highlight the effects of different metal centres and ligands on electrocatalysis. The application of MOFs in electrochemistry is a relatively new field making the findings of this study a significant addition to the body of knowledge.
- Full Text:
- Authors: Murinzi, Tafadzwa Wendy
- Date: 2020
- Subjects: Electrochemistry , Metal-organic frameworks , Polyoxometalates , Fourier transform infrared spectroscopy , Electrocatalysis , Cysteine
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/167598 , vital:41495
- Description: Metal organic frameworks (MOFs) have received a lot of attention over the past few years due to their vast range of interesting properties and applications, such as catalysis, environmental sensing and storage. This wide range of potential applications is afforded by careful selection and manipulation of the components chosen in assembling of MOFs. In this study, three series of MOFs were synthesized from Co(II), Cu(II) and Mo(VI) polyoxometallates with either 1,3,5-benzenetricarboxylic acid, 1,2,4,5-benzenetetracarboxylic acid or 2,6- pyridinedicarboxylic acid as the ligands. In series 1, the common 1,3,5- benzenetricarboxylic acid MOF, HKUST-1, and POM modified HKUST-1 compounds involving encapsulation and encorporation of the POM were utilised. In series 2, flexible cobalt(II) benzenepolycarboxylate MOFs which investigated the effect of varying the degree of carboxylate substituent were utilised. In series 3, flexibly reduced heterocyclic polycarboxylate MOFs using 2,6-pyridine dicarboxylate were utilised. Solvothermal and slow evaporation synthesis conditions were employed. Where single crystals of good quality were produced, single crystal X-ray diffraction (SC-XRD) was employed for structural elucidation. In the absence of such crystals, a combination of elemental analysis, inductively coupled plasma optical emission spectrometry (ICP-OES) and powder X-ray diffraction (PXRD) was used. Characterization of the MOFs was done by Fourier transform infrared spectrometry (FTIR) and thermal methods, namely thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The electrocatalytic potential of the compounds in the oxidation of L-cysteine was then investigated using a variety of techniques. Cyclic voltammetry was used for L-cysteine detection whilst chronoamperometry and differential pulse voltammetry were used to determine the nanoprobes’ sensitivity, rate constants and detection limits. Electrochemical impedence spectroscopy was used to investigate the charge transfer resistance (RCT) and electron transfer kinetics. Of the three, series 3 gave the best signals and sensitivities for electrocatalysis of L-cysteine followed by series 2 and lastly series 1. Series 2 showed the highest stability and series 1 required the least overpotential. The results highlight the effects of different metal centres and ligands on electrocatalysis. The application of MOFs in electrochemistry is a relatively new field making the findings of this study a significant addition to the body of knowledge.
- Full Text:
- «
- ‹
- 1
- ›
- »