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
Investigations into the asymmetric reduction of ketones
- Authors: Bena, Luvuyo Clifford
- Date: 2003
- Subjects: Ketones , Asymmetric synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:11065 , http://hdl.handle.net/10948/323 , Ketones , Asymmetric synthesis
- Description: A six-step synthesis of salbutamol from methyl salicylate with an overall yield of 17% has been completed, although the yield was not optimised. In the process, Zn(BH4)2 was found to selectively reduce a ketone carbonyl group in the presence of an ester unit. In contrast, borane was found to reduce both the ketone and ester carbonyl groups. Reduction of phenacyl bromide with borane in the presence of chiral catalysts based on (R)-alaninol and (R,S)-ephidrine resulted a measure of enantioselectivity in the product. However, the configuration of the alcohol obtained in the case of (R)-alaninol was contrary to expectations based both on experimental trends observed elsewhere as well as our own theoretical predictions. The asymmetric reduction of methyl 5-bromoacetyl-2-benzyloxybenzoate was accomplished with both borane and Zn(BH4)2 in the presence of a range of chiral catalysts. Optically active products were obtained in all cases, although the optical rotations were significantly smaller in the case of Zn(BH4)2. Unfortunately, we were not successful in determining the enantiomeric excesses of these reactions. The use of a NMR lanthanide shift reagent resulted in a complex spectrum that was impossible to interpret unambiguously. This presumably arises from the presence of several Lewis base sites in the product at which complexation with the shift reagent can take place. It was also not possible to determine the optical rotation of salbutamol itself owing to the relatively small amount of material obtained. A conformational analysis of salbutamol, where NMR data was correlated with molecular modelling results, was successfully carried out and revealed a strong preference for that conformer family characterised by O–C–C–N and Ar–C–C–N torsion angles of ca. 60º and 180º, respectively. Interestingly, these conformers are found to be stabilised by OH…N rather than NH…O hydrogen bonding. This study has also confirmed the effectiveness of the MMFF94 force field for conformational analysis studies in compounds of this kind. Lastly, a relatively simple method for modelling the BH3/oxazaborolidine reduction of ketones at the PM3 semiempirical MO level of approximation was devised. This approach has provided insights into the mechanism of the reaction and has furthermore enabled us to predict the enantioselectivities likely to result from various catalysts and ketones. In comparing our theoretical and experimental findings, an anomalous result was observed in the case of (R)-alaninol; this will have to be investigated further, particularly at the experimental level. However, we believe that our approach provides a sound basis for aiding the design and screening of new, potentially better catalysts.
- Full Text:
- Date Issued: 2003
- Authors: Bena, Luvuyo Clifford
- Date: 2003
- Subjects: Ketones , Asymmetric synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:11065 , http://hdl.handle.net/10948/323 , Ketones , Asymmetric synthesis
- Description: A six-step synthesis of salbutamol from methyl salicylate with an overall yield of 17% has been completed, although the yield was not optimised. In the process, Zn(BH4)2 was found to selectively reduce a ketone carbonyl group in the presence of an ester unit. In contrast, borane was found to reduce both the ketone and ester carbonyl groups. Reduction of phenacyl bromide with borane in the presence of chiral catalysts based on (R)-alaninol and (R,S)-ephidrine resulted a measure of enantioselectivity in the product. However, the configuration of the alcohol obtained in the case of (R)-alaninol was contrary to expectations based both on experimental trends observed elsewhere as well as our own theoretical predictions. The asymmetric reduction of methyl 5-bromoacetyl-2-benzyloxybenzoate was accomplished with both borane and Zn(BH4)2 in the presence of a range of chiral catalysts. Optically active products were obtained in all cases, although the optical rotations were significantly smaller in the case of Zn(BH4)2. Unfortunately, we were not successful in determining the enantiomeric excesses of these reactions. The use of a NMR lanthanide shift reagent resulted in a complex spectrum that was impossible to interpret unambiguously. This presumably arises from the presence of several Lewis base sites in the product at which complexation with the shift reagent can take place. It was also not possible to determine the optical rotation of salbutamol itself owing to the relatively small amount of material obtained. A conformational analysis of salbutamol, where NMR data was correlated with molecular modelling results, was successfully carried out and revealed a strong preference for that conformer family characterised by O–C–C–N and Ar–C–C–N torsion angles of ca. 60º and 180º, respectively. Interestingly, these conformers are found to be stabilised by OH…N rather than NH…O hydrogen bonding. This study has also confirmed the effectiveness of the MMFF94 force field for conformational analysis studies in compounds of this kind. Lastly, a relatively simple method for modelling the BH3/oxazaborolidine reduction of ketones at the PM3 semiempirical MO level of approximation was devised. This approach has provided insights into the mechanism of the reaction and has furthermore enabled us to predict the enantioselectivities likely to result from various catalysts and ketones. In comparing our theoretical and experimental findings, an anomalous result was observed in the case of (R)-alaninol; this will have to be investigated further, particularly at the experimental level. However, we believe that our approach provides a sound basis for aiding the design and screening of new, potentially better catalysts.
- Full Text:
- Date Issued: 2003
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