Insights: elucidation of squalene monooxygenase inhibitors for lowering cholesterol in cardiovascular diseases
- Authors: Leoma, Mofeli Benedict
- Date: 2024-04-04
- Subjects: Squalene monooxygenase , Cholesterol , Cardiovascular system Diseases , Anticholesteremic agents , Molecular dynamics , High throughput screening (Drug development) , Molecular Docking
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/434861 , vital:73111
- Description: Statins have been used to lower high cholesterol levels in the past few decades. However, several studies have shown that some people taking statins experience side effects over time, especially elderly patients, women of childbirth possibility, and children. Several studies have shown that the majority of people with underlying cardiovascular complications caused by high cholesterol are at a greater risk of fatality due to COVID-19, regardless of age and sex. The literature suggests that antimycotic squalene monooxygenase inhibitors, terbinafine and its derivatives, and anticholesterolemic squalene monooxygenase (SM) inhibitors could be another option and a safer remedy for lowering cholesterol in mammals. Molecular docking calculations, molecular dynamics (MD) simulations, molecular mechanics generalized born surface area (MM-GBSA) calculations, quantum mechanics/molecular mechanics calculations (QM/MM), and density functional theory (DFT) calculations were used in this study. An early stage in drug discovery, in which small molecular hits from high- throughput screening (HTS) are evaluated and undergo limited optimization to identify promising lead compounds, is referred to as lead generation. To address the first step of lead generation, the number of compounds to be tested was narrowed down, and the hit compounds that could be taken for further tests were obtained. Thus, the molecular docking technique was taken advantage of, which assisted us in identifying the antimycotic ligand SDZ 18, which had a good binding affinity of about -8,4 kcal mol−1. Another widely employed strategy, the molecular mechanics-generalized born surface area (MM-GBSA), was used to investigate the binding free energies of the protein-ligand complexes to validate the binding affinities obtained from molecular docking. Despite the excellent docking results, it must be emphasized that the stability of the ligand in the binding pocket must be investigated. To address this, the protein-ligand complexes were then taken through molecular dynamics for 100 ns simulations calculations which showed that the inhibitors stayed in the binding pocket with the RMSD values below 3.5 Å for most systems. This provided insight into a realistic model because the docked complexes were placed in conditions closer to the physiological environment at 300 K and 1.01325 bar, and in an explicitly solvated dynamic environment. Density functional theory (DFT) at the B3LPY level of theory using the standard 6-31G(d,p) basis set was used to assess the reactivity and other properties of the SM inhibitors. ONIOM calculations were performed to explain what was happening at the microscopic level by calculating the total energy of the complex. The aim of this project was to efficiently uncover the non-physical aspects of SM inhibitors with the help of computational techniques to identify new drugs that can lower high cholesterol levels. From a theoretical perspective, the results obtained from docking indicated that the antimycotic ligands SDZ SBA 586 18 and TNSA 84 (trisnor-squalene alcohol ) have good binding affinities, and the MM-GBSA method provided free energy calculations. MD results indicated that the stability of the ligand in the binding pocket was achieved during the 100 ns simulations. The HOMO-LUMO energy gaps obtained from DFT calculations provided information on the reactivity of the ligands. Other insights into the protein-ligand complexes were obtained from a hybrid ONIOM QM/MM study. , Thesis (MSc) -- Faculty of Science, Chemistry, 2024
- Full Text:
- Date Issued: 2024-04-04
- Authors: Leoma, Mofeli Benedict
- Date: 2024-04-04
- Subjects: Squalene monooxygenase , Cholesterol , Cardiovascular system Diseases , Anticholesteremic agents , Molecular dynamics , High throughput screening (Drug development) , Molecular Docking
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/434861 , vital:73111
- Description: Statins have been used to lower high cholesterol levels in the past few decades. However, several studies have shown that some people taking statins experience side effects over time, especially elderly patients, women of childbirth possibility, and children. Several studies have shown that the majority of people with underlying cardiovascular complications caused by high cholesterol are at a greater risk of fatality due to COVID-19, regardless of age and sex. The literature suggests that antimycotic squalene monooxygenase inhibitors, terbinafine and its derivatives, and anticholesterolemic squalene monooxygenase (SM) inhibitors could be another option and a safer remedy for lowering cholesterol in mammals. Molecular docking calculations, molecular dynamics (MD) simulations, molecular mechanics generalized born surface area (MM-GBSA) calculations, quantum mechanics/molecular mechanics calculations (QM/MM), and density functional theory (DFT) calculations were used in this study. An early stage in drug discovery, in which small molecular hits from high- throughput screening (HTS) are evaluated and undergo limited optimization to identify promising lead compounds, is referred to as lead generation. To address the first step of lead generation, the number of compounds to be tested was narrowed down, and the hit compounds that could be taken for further tests were obtained. Thus, the molecular docking technique was taken advantage of, which assisted us in identifying the antimycotic ligand SDZ 18, which had a good binding affinity of about -8,4 kcal mol−1. Another widely employed strategy, the molecular mechanics-generalized born surface area (MM-GBSA), was used to investigate the binding free energies of the protein-ligand complexes to validate the binding affinities obtained from molecular docking. Despite the excellent docking results, it must be emphasized that the stability of the ligand in the binding pocket must be investigated. To address this, the protein-ligand complexes were then taken through molecular dynamics for 100 ns simulations calculations which showed that the inhibitors stayed in the binding pocket with the RMSD values below 3.5 Å for most systems. This provided insight into a realistic model because the docked complexes were placed in conditions closer to the physiological environment at 300 K and 1.01325 bar, and in an explicitly solvated dynamic environment. Density functional theory (DFT) at the B3LPY level of theory using the standard 6-31G(d,p) basis set was used to assess the reactivity and other properties of the SM inhibitors. ONIOM calculations were performed to explain what was happening at the microscopic level by calculating the total energy of the complex. The aim of this project was to efficiently uncover the non-physical aspects of SM inhibitors with the help of computational techniques to identify new drugs that can lower high cholesterol levels. From a theoretical perspective, the results obtained from docking indicated that the antimycotic ligands SDZ SBA 586 18 and TNSA 84 (trisnor-squalene alcohol ) have good binding affinities, and the MM-GBSA method provided free energy calculations. MD results indicated that the stability of the ligand in the binding pocket was achieved during the 100 ns simulations. The HOMO-LUMO energy gaps obtained from DFT calculations provided information on the reactivity of the ligands. Other insights into the protein-ligand complexes were obtained from a hybrid ONIOM QM/MM study. , Thesis (MSc) -- Faculty of Science, Chemistry, 2024
- Full Text:
- Date Issued: 2024-04-04
Synthesis, characterization and in vitro biological studies of cholesterol-based carriers as potential therapeutic agents
- Authors: Ruwizhi, Ngonidzashe
- Date: 2021-03
- Subjects: Drug delivery systems , Cholesterol
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10353/20708 , vital:46443
- Description: Malaria, cancer and bacterial infections are numbered among the highest causes of fatalities. Most of the drugs used to combat these diseases suffer from resistance, poor absorption and bioavailability and high toxicity. Therefore, delivering a drug requires an excellent drug delivery system that must provide the medication at the site of action in the minimum time possible. Cholesterol is a sterol that is abundantly found in the human body and forms a part in the structure and organization of cell membranes. Many researchers have used cholesterol, especially in organic synthesis, because of its ready availability, low cost and functional groups that can be readily derivatized. In this research, different therapeutic agents (anticancer, antimalarial and antibacterial) were conjugated to cholesterol, and the synthesized compounds were characterized using FTIR, 1H and 13C NMR, Mass Spectroscopy, 2D 1H-13C, HSQC NMR and tested for in vitro biological activity. Thirteen compounds were successfully synthesized. CHS-Cur was the most effective against all Gram-positive bacterial strains, while CHS-Cur, CHS-ZD and C-CAC-ZD were effective against all the bacterial strains. C-CAC-Pyr showed good antiplasmodial activity with 97.75 and 97.83% inhibition at 20 and 10 μg/ml concentrations, respectively. The biological activity of some of the compounds was increased by the conjugation of cholesterol, while others displayed reduced biological activity. In vitro cytotoxicity of the synthesized compounds on HeLa (cervical cancer) cells showed that compounds 2 (7.559 μg/mL), 3 (5.840 μg/mL), 5 (1.44 mg/mL), 7 (4.308 μg/mL) and 11 (3.295 μg/mL) exhibited some good anticancer activity with IC50 values of less than 10 μg/mL. Treating T3T fibroblast cells with compounds 2, 4, 5, 6, and 10 did not reveal a cytotoxic effect on the normal cells when compared to the control, cisplatin. , Thesis (MSc) (Chemistry) -- University of Fort Hare, 2021
- Full Text:
- Date Issued: 2021-03
- Authors: Ruwizhi, Ngonidzashe
- Date: 2021-03
- Subjects: Drug delivery systems , Cholesterol
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10353/20708 , vital:46443
- Description: Malaria, cancer and bacterial infections are numbered among the highest causes of fatalities. Most of the drugs used to combat these diseases suffer from resistance, poor absorption and bioavailability and high toxicity. Therefore, delivering a drug requires an excellent drug delivery system that must provide the medication at the site of action in the minimum time possible. Cholesterol is a sterol that is abundantly found in the human body and forms a part in the structure and organization of cell membranes. Many researchers have used cholesterol, especially in organic synthesis, because of its ready availability, low cost and functional groups that can be readily derivatized. In this research, different therapeutic agents (anticancer, antimalarial and antibacterial) were conjugated to cholesterol, and the synthesized compounds were characterized using FTIR, 1H and 13C NMR, Mass Spectroscopy, 2D 1H-13C, HSQC NMR and tested for in vitro biological activity. Thirteen compounds were successfully synthesized. CHS-Cur was the most effective against all Gram-positive bacterial strains, while CHS-Cur, CHS-ZD and C-CAC-ZD were effective against all the bacterial strains. C-CAC-Pyr showed good antiplasmodial activity with 97.75 and 97.83% inhibition at 20 and 10 μg/ml concentrations, respectively. The biological activity of some of the compounds was increased by the conjugation of cholesterol, while others displayed reduced biological activity. In vitro cytotoxicity of the synthesized compounds on HeLa (cervical cancer) cells showed that compounds 2 (7.559 μg/mL), 3 (5.840 μg/mL), 5 (1.44 mg/mL), 7 (4.308 μg/mL) and 11 (3.295 μg/mL) exhibited some good anticancer activity with IC50 values of less than 10 μg/mL. Treating T3T fibroblast cells with compounds 2, 4, 5, 6, and 10 did not reveal a cytotoxic effect on the normal cells when compared to the control, cisplatin. , Thesis (MSc) (Chemistry) -- University of Fort Hare, 2021
- Full Text:
- Date Issued: 2021-03
- «
- ‹
- 1
- ›
- »