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:
- Date Issued: 2020
- 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:
- Date Issued: 2020
Investigating how outdoor environmental education programmes in South Africa respond to the needs of visually impaired learners via inclusive practices
- Authors: Eksteen, Hendrik Christiaan
- Date: 2019
- Subjects: Children with visual disabilities -- Education -- South Africa , Outdoor education -- South Africa , Environmental education -- South Africa , Outdoor recreation for children with disabilities -- South Africa , Inclusive education -- South Africa
- Language: English
- Type: text , Thesis , Masters , MEd
- Identifier: http://hdl.handle.net/10962/92716 , vital:30721
- Description: Outdoor environmental education programmes in South Africa are conducted at campsites and centres owned by the government, non-profit organisations and private owners. People suffering from impairments are often disabled by society because of their handicap. More than three percent (3%) of young people in South Africa aged between 10 – 19 years are disabled. This study investigates the status of inclusion of outdoor environmental education programmes for disabled young people; what is offered and what practices are working in the industry in South Africa. It also investigates barriers to inclusion. Though many disabilities have been identified, visual impairment is the focus of the study. This study also looks at what more can be done from an Ecological Systems Theory of Human Development point of view and investigates what underlying mechanisms influence the inclusion of visually impaired individuals in outdoor environmental education programmes in South Africa. What is done and what is not done to promote inclusion for visually impaired learners in these programmes is also investigated. This study aims to answer the question; What is the current status quo concerning the inclusion of visually impaired learners in outdoor environmental learning programmes in environmental education centres and campsites in South Africa? An initial focus group conducted informally prior to the study, helped me to understand the context. In this study, key-interviews and questionnaires were used as research tools. I also ran a photo narrative project throughout the research project which was used as a participatory activity and provided further insight into practices. Inductive, abductive and retroductive analysis approaches were used to identify emerging themes, and I applied method triangulation using all research tools in order to address the research questions. Some of the most important findings are that: • There are many barriers, some intrinsic others extrinsic, that hinder inclusion of visually impaired individuals in outdoor environmental education programmes in South Africa. • Although there are many things done in the industry to promote inclusion, there is much more that could be done. • The visually impaired individual him/herself influences inclusivity in outdoor environmental education programmes. • Interactions and influences in the mesosystem (between different microsystems and ecosystems) have an impact on the inclusivity of visually impaired individuals in outdoor environmental education programmes. • Dispositions of people have an impact on the inclusion of visually impaired individuals in outdoor environmental education programmes. • The diversity of generative mechanisms (drivers to events), that interact at the level of the real, influence the inclusion of visually impaired individuals in outdoor environmental education programmes. Disability/impairment is a much-neglected area of environmental education research in South Africa. This study has contributed scholarship to this area and has also identified possible further areas of study in creating awareness, creating an opportunity to reflect on practices, and finding possible solutions to the barriers of exclusion.
- Full Text:
- Date Issued: 2019
- Authors: Eksteen, Hendrik Christiaan
- Date: 2019
- Subjects: Children with visual disabilities -- Education -- South Africa , Outdoor education -- South Africa , Environmental education -- South Africa , Outdoor recreation for children with disabilities -- South Africa , Inclusive education -- South Africa
- Language: English
- Type: text , Thesis , Masters , MEd
- Identifier: http://hdl.handle.net/10962/92716 , vital:30721
- Description: Outdoor environmental education programmes in South Africa are conducted at campsites and centres owned by the government, non-profit organisations and private owners. People suffering from impairments are often disabled by society because of their handicap. More than three percent (3%) of young people in South Africa aged between 10 – 19 years are disabled. This study investigates the status of inclusion of outdoor environmental education programmes for disabled young people; what is offered and what practices are working in the industry in South Africa. It also investigates barriers to inclusion. Though many disabilities have been identified, visual impairment is the focus of the study. This study also looks at what more can be done from an Ecological Systems Theory of Human Development point of view and investigates what underlying mechanisms influence the inclusion of visually impaired individuals in outdoor environmental education programmes in South Africa. What is done and what is not done to promote inclusion for visually impaired learners in these programmes is also investigated. This study aims to answer the question; What is the current status quo concerning the inclusion of visually impaired learners in outdoor environmental learning programmes in environmental education centres and campsites in South Africa? An initial focus group conducted informally prior to the study, helped me to understand the context. In this study, key-interviews and questionnaires were used as research tools. I also ran a photo narrative project throughout the research project which was used as a participatory activity and provided further insight into practices. Inductive, abductive and retroductive analysis approaches were used to identify emerging themes, and I applied method triangulation using all research tools in order to address the research questions. Some of the most important findings are that: • There are many barriers, some intrinsic others extrinsic, that hinder inclusion of visually impaired individuals in outdoor environmental education programmes in South Africa. • Although there are many things done in the industry to promote inclusion, there is much more that could be done. • The visually impaired individual him/herself influences inclusivity in outdoor environmental education programmes. • Interactions and influences in the mesosystem (between different microsystems and ecosystems) have an impact on the inclusivity of visually impaired individuals in outdoor environmental education programmes. • Dispositions of people have an impact on the inclusion of visually impaired individuals in outdoor environmental education programmes. • The diversity of generative mechanisms (drivers to events), that interact at the level of the real, influence the inclusion of visually impaired individuals in outdoor environmental education programmes. Disability/impairment is a much-neglected area of environmental education research in South Africa. This study has contributed scholarship to this area and has also identified possible further areas of study in creating awareness, creating an opportunity to reflect on practices, and finding possible solutions to the barriers of exclusion.
- Full Text:
- Date Issued: 2019
The use of the female voice in three novels by J.M. Coetzee
- Authors: Graham, Lucy Valerie
- Date: 1997
- Subjects: Coetzee, J. M., 1940- -- Criticism and interpretation , Coetzee, J. M., 1940- Foe , Coetzee, J. M., 1940- In the heart of the country , Coetzee, J. M., 1940- Age Of Iron , Women in literature , Voice in literature
- Language: English
- Type: Thesis , Masters , MA
- Identifier: vital:2224 , http://hdl.handle.net/10962/d1002267 , Coetzee, J. M., 1940- -- Criticism and interpretation , Coetzee, J. M., 1940- Foe , Coetzee, J. M., 1940- In the heart of the country , Coetzee, J. M., 1940- Age Of Iron , Women in literature , Voice in literature
- Description: This study investigates J.M. Coetzee's use of the female voice in In the Heart of the Country, Foe and Age of Iron, and is based on the premise that Coetzee's position as a male author using a female voice is important for readings of these novels. Although the implications of Coetzee's strategy are examined against the theoretical background of feminist or gender-related discourses, this study does not attempt to claim Coetzee for feminism, nor to prove him a misogynist. Instead, it focuses on the specific positional and narrative possibilities afforded by Coetzee's use of a female voice. Chapter One comments on the fact that Coetzee's strategy of "textual cross-dressing" has not been given much critical attention in the past, observing that research on South African literature has largely been limited to studies of racial and colonial problematics. This introductory chapter mentions that the different female narrators in Coetzee's novels articulate aspects of a discourse in crisis, resulting in profound ambivalence in their representation. Chapter Two observes that the female voices in Coetzee's novels invoke the textual illusion of a speaking/writing female body, and explains that this is useful in expressing aspects of what Coetzee refers to as the suffering body. Although Coetzee appropriates a female narrative position and employs certain subversive textual elements associated with "the feminine", attempts made by certain critics to label Coetzee's writing as ecriture feminine are rejected as highly problematic. Instead, the study contends that the femaleness of the narrators relative to "masculine" discursive power enables Coetzee to perform a critique of power "from a position of weakness". Furthermore, the presence of certain "feminine" elements within these narrators suggests Coetzee's affiliation with characteristics derided within phallocratic discourses, and becomes a strategic means of fictive self-positioning, of figuring his own position as a dissident. Chapter Three is a study of In the Heart of the Country, and proposes that Magda is represented as a typical nineteenth century hysteric. Her hystericized narrative is linked to certain avant-garde narratives, such as the nouveau roman and "New Wave" cinematography, both cited by Coetzee as influences on the novel. Furthermore, the novel provides insight into the ambiguous role of the hysteric and dramatises the position of the dissident: on a discursive level Magda's narrative is subversive, and yet in terms of social "reality" her revolt is ineffectual. Chapter Four addresses the issue of author-ity in Foe, and draws on Coetzee's affiliation with Susan Barton, the struggling authoress, whose narrative reveals the levels of power and authority operating within, novelistic discourse when she asks "Who ,is speaking me?". The study observes that Foe also performs a critique of the power-seeking project of liberal feminism, as the novel sets Susan's quest for authorship against the background of a more radical "otherness", that of Friday. Chapter Five asserts that Age of Iron exploits the ethical possibilities of a maternal discourse. Tracing parallels between images of motherhood in psychoanalytic feminism and in Age of Iron, this chapter argues that Kristeva's theory of abjection is relevant for a reading of Elizabeth Curren's position as a mother who has cancer. The childbirth metaphor as it appears in Age- of Iron becomes an alternative and profoundly ethical way of figuring the process of novel writing.
- Full Text:
- Date Issued: 1997
- Authors: Graham, Lucy Valerie
- Date: 1997
- Subjects: Coetzee, J. M., 1940- -- Criticism and interpretation , Coetzee, J. M., 1940- Foe , Coetzee, J. M., 1940- In the heart of the country , Coetzee, J. M., 1940- Age Of Iron , Women in literature , Voice in literature
- Language: English
- Type: Thesis , Masters , MA
- Identifier: vital:2224 , http://hdl.handle.net/10962/d1002267 , Coetzee, J. M., 1940- -- Criticism and interpretation , Coetzee, J. M., 1940- Foe , Coetzee, J. M., 1940- In the heart of the country , Coetzee, J. M., 1940- Age Of Iron , Women in literature , Voice in literature
- Description: This study investigates J.M. Coetzee's use of the female voice in In the Heart of the Country, Foe and Age of Iron, and is based on the premise that Coetzee's position as a male author using a female voice is important for readings of these novels. Although the implications of Coetzee's strategy are examined against the theoretical background of feminist or gender-related discourses, this study does not attempt to claim Coetzee for feminism, nor to prove him a misogynist. Instead, it focuses on the specific positional and narrative possibilities afforded by Coetzee's use of a female voice. Chapter One comments on the fact that Coetzee's strategy of "textual cross-dressing" has not been given much critical attention in the past, observing that research on South African literature has largely been limited to studies of racial and colonial problematics. This introductory chapter mentions that the different female narrators in Coetzee's novels articulate aspects of a discourse in crisis, resulting in profound ambivalence in their representation. Chapter Two observes that the female voices in Coetzee's novels invoke the textual illusion of a speaking/writing female body, and explains that this is useful in expressing aspects of what Coetzee refers to as the suffering body. Although Coetzee appropriates a female narrative position and employs certain subversive textual elements associated with "the feminine", attempts made by certain critics to label Coetzee's writing as ecriture feminine are rejected as highly problematic. Instead, the study contends that the femaleness of the narrators relative to "masculine" discursive power enables Coetzee to perform a critique of power "from a position of weakness". Furthermore, the presence of certain "feminine" elements within these narrators suggests Coetzee's affiliation with characteristics derided within phallocratic discourses, and becomes a strategic means of fictive self-positioning, of figuring his own position as a dissident. Chapter Three is a study of In the Heart of the Country, and proposes that Magda is represented as a typical nineteenth century hysteric. Her hystericized narrative is linked to certain avant-garde narratives, such as the nouveau roman and "New Wave" cinematography, both cited by Coetzee as influences on the novel. Furthermore, the novel provides insight into the ambiguous role of the hysteric and dramatises the position of the dissident: on a discursive level Magda's narrative is subversive, and yet in terms of social "reality" her revolt is ineffectual. Chapter Four addresses the issue of author-ity in Foe, and draws on Coetzee's affiliation with Susan Barton, the struggling authoress, whose narrative reveals the levels of power and authority operating within, novelistic discourse when she asks "Who ,is speaking me?". The study observes that Foe also performs a critique of the power-seeking project of liberal feminism, as the novel sets Susan's quest for authorship against the background of a more radical "otherness", that of Friday. Chapter Five asserts that Age of Iron exploits the ethical possibilities of a maternal discourse. Tracing parallels between images of motherhood in psychoanalytic feminism and in Age of Iron, this chapter argues that Kristeva's theory of abjection is relevant for a reading of Elizabeth Curren's position as a mother who has cancer. The childbirth metaphor as it appears in Age- of Iron becomes an alternative and profoundly ethical way of figuring the process of novel writing.
- Full Text:
- Date Issued: 1997
- «
- ‹
- 1
- ›
- »