Identification of possible natural compounds as potential inhibitors against Plasmodium M1 alanyl aminopeptidase
- Soliman, Omar Samir Abdel Ghaffar
- Authors: Soliman, Omar Samir Abdel Ghaffar
- Date: 2019
- Subjects: Plasmodium , Malaria -- Chemotherapy , Plasmodium -- Inhibitors , Drug resistance in microorganisms , Aminopeptidases
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/72284 , vital:30026
- Description: Malaria is a major tropical health problem with a 29% mortality rate among people of all ages; it also affects 35% of the children. Despite the decrease in mortality rate in recent years, malaria still results in around 2000 deaths per day. Malaria is caused by Plasmodium parasites and is transmitted to humans via the bites from infected female Anopheles mosquitoes during blood meals. There are five different Plasmodium species that can cause human malaria, which include Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi. Among these five species, the most pathogenic ones are Plasmodium falciparum and Plasmodium vivax. Malaria is usually hard to diagnose because the symptoms are not exclusive to malaria and very similar to flu, e.g., fever, muscle pain, and chills, which lead to the misdiagnosis of malaria cases. Malaria is lethal if not treated because it can cause severe complications in the respiratory tract, liver, metabolic acidosis, and hypoglycemia. The malaria parasite life cycle includes two types of hosts, i.e., a human host and female Anopheles mosquito host. Malaria continuously develops resistance to the available drugs, which is one of the major challenges in disease control. This situation confirms the need to develop new drugs that target virulence factors of malaria. The malarial parasite has three main life cycle stages, which include the host liver stage, host blood stage and vector stage. In the blood stage, parasites degrade hemoglobin to amino acids, which is important as these parasites cannot produce their own amino acids. Different proteases are involved in this hemoglobin degradation process. M1 alanyl aminopeptidase is one of these proteases involved at the end of hemoglobin degradation. This study focused on M1 alanyl aminopeptidase as a potential drug target. M1 alanyl aminopeptidase consists of four domains: N-terminal domain, catalytic domain, middle domain and C-terminal domain. The catalytic domain remains conserved among different Plasmodium species. Inhibition of this enzyme might prevent Plasmodium growth as it can’t produce its own amino acids. In this study, sequence analysis was carried out in both human and Plasmodium M1 alanyl aminopeptidase to identify conserved and divergent regions between them. 3D protein models of the M1 alanyl aminopeptidase from Plasmodium species were built and validated. Then the generated models were used for virtual screening against 623 compounds retrieved from the South African Natural Compounds Database (SANCDB, https://sancdb.rubi.ru.ac.za/). Virtual screening was done using blind and targeted docking methods. Docking was used to identify compounds with selective high binding affinity to the active site of the parasite protein. In this study, one SANCDB compound was selected for each protein: SANC00531 was selected against P. falciparum M1 alanyl aminopeptidase, SANC00469 against P. knowlesi, SANC00660 against P. vivax, SANC00144 against P. ovale and SANC00109 against P. malariae. It was found that Plamsodium M1 alanyl aminopeptidase can be used as a potential drug target as it showed selective binding against different inhibitor compounds. This result will be investigated in future work though molecular dynamic analysis to investigate the stability of protein-ligand complexes.
- Full Text:
- Date Issued: 2019
- Authors: Soliman, Omar Samir Abdel Ghaffar
- Date: 2019
- Subjects: Plasmodium , Malaria -- Chemotherapy , Plasmodium -- Inhibitors , Drug resistance in microorganisms , Aminopeptidases
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/72284 , vital:30026
- Description: Malaria is a major tropical health problem with a 29% mortality rate among people of all ages; it also affects 35% of the children. Despite the decrease in mortality rate in recent years, malaria still results in around 2000 deaths per day. Malaria is caused by Plasmodium parasites and is transmitted to humans via the bites from infected female Anopheles mosquitoes during blood meals. There are five different Plasmodium species that can cause human malaria, which include Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi. Among these five species, the most pathogenic ones are Plasmodium falciparum and Plasmodium vivax. Malaria is usually hard to diagnose because the symptoms are not exclusive to malaria and very similar to flu, e.g., fever, muscle pain, and chills, which lead to the misdiagnosis of malaria cases. Malaria is lethal if not treated because it can cause severe complications in the respiratory tract, liver, metabolic acidosis, and hypoglycemia. The malaria parasite life cycle includes two types of hosts, i.e., a human host and female Anopheles mosquito host. Malaria continuously develops resistance to the available drugs, which is one of the major challenges in disease control. This situation confirms the need to develop new drugs that target virulence factors of malaria. The malarial parasite has three main life cycle stages, which include the host liver stage, host blood stage and vector stage. In the blood stage, parasites degrade hemoglobin to amino acids, which is important as these parasites cannot produce their own amino acids. Different proteases are involved in this hemoglobin degradation process. M1 alanyl aminopeptidase is one of these proteases involved at the end of hemoglobin degradation. This study focused on M1 alanyl aminopeptidase as a potential drug target. M1 alanyl aminopeptidase consists of four domains: N-terminal domain, catalytic domain, middle domain and C-terminal domain. The catalytic domain remains conserved among different Plasmodium species. Inhibition of this enzyme might prevent Plasmodium growth as it can’t produce its own amino acids. In this study, sequence analysis was carried out in both human and Plasmodium M1 alanyl aminopeptidase to identify conserved and divergent regions between them. 3D protein models of the M1 alanyl aminopeptidase from Plasmodium species were built and validated. Then the generated models were used for virtual screening against 623 compounds retrieved from the South African Natural Compounds Database (SANCDB, https://sancdb.rubi.ru.ac.za/). Virtual screening was done using blind and targeted docking methods. Docking was used to identify compounds with selective high binding affinity to the active site of the parasite protein. In this study, one SANCDB compound was selected for each protein: SANC00531 was selected against P. falciparum M1 alanyl aminopeptidase, SANC00469 against P. knowlesi, SANC00660 against P. vivax, SANC00144 against P. ovale and SANC00109 against P. malariae. It was found that Plamsodium M1 alanyl aminopeptidase can be used as a potential drug target as it showed selective binding against different inhibitor compounds. This result will be investigated in future work though molecular dynamic analysis to investigate the stability of protein-ligand complexes.
- Full Text:
- Date Issued: 2019
In silico study of Plasmodium 1-deoxy-dxylulose 5-phosphate reductoisomerase (DXR) for identification of novel inhibitors from SANCDB
- Authors: Diallo, Bakary N'tji
- Date: 2018
- Subjects: Plasmodium 1-deoxy-dxylulose 5-phosphate reductoisomerase , Isoprenoids , Plasmodium , Antimalarials , Malaria -- Chemotherapy , Molecules -- Models , Molecular dynamics , South African Natural Compounds Database
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/64012 , vital:28523
- Description: Malaria remains a major health concern with a complex parasite constantly developing resistance to the different drugs introduced to treat it, threatening the efficacy of the current ACT treatment recommended by WHO (World Health Organization). Different antimalarial compounds with different mechanisms of action are ideal as this decreases chances of resistance occurring. Inhibiting DXR and consequently the MEP pathway is a good strategy to find a new antimalarial with a novel mode of action. From literature, all the enzymes of the MEP pathway have also been shown to be indispensable for the synthesis of isoprenoids. They have been validated as drug targets and the X-ray structure of each of the enzymes has been solved. DXR is a protein which catalyses the second step of the MEP pathway. There are currently 255 DXR inhibitors in the Binding Database (accessed November 2017) generally based on the fosmidomycin structural scaffold and thus often showing poor drug likeness properties. This study aims to research new DXR inhibitors using in silico techniques. We analysed the protein sequence and built 3D models in close and open conformations for the different Plasmodium sequences. Then SANCDB compounds were screened to identify new potential DXR inhibitors with new chemical scaffolds. Finally, the identified hits were submitted to molecular dynamics studies, preceded by a parameterization of the manganese atom in the protein active site.
- Full Text:
- Date Issued: 2018
- Authors: Diallo, Bakary N'tji
- Date: 2018
- Subjects: Plasmodium 1-deoxy-dxylulose 5-phosphate reductoisomerase , Isoprenoids , Plasmodium , Antimalarials , Malaria -- Chemotherapy , Molecules -- Models , Molecular dynamics , South African Natural Compounds Database
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/64012 , vital:28523
- Description: Malaria remains a major health concern with a complex parasite constantly developing resistance to the different drugs introduced to treat it, threatening the efficacy of the current ACT treatment recommended by WHO (World Health Organization). Different antimalarial compounds with different mechanisms of action are ideal as this decreases chances of resistance occurring. Inhibiting DXR and consequently the MEP pathway is a good strategy to find a new antimalarial with a novel mode of action. From literature, all the enzymes of the MEP pathway have also been shown to be indispensable for the synthesis of isoprenoids. They have been validated as drug targets and the X-ray structure of each of the enzymes has been solved. DXR is a protein which catalyses the second step of the MEP pathway. There are currently 255 DXR inhibitors in the Binding Database (accessed November 2017) generally based on the fosmidomycin structural scaffold and thus often showing poor drug likeness properties. This study aims to research new DXR inhibitors using in silico techniques. We analysed the protein sequence and built 3D models in close and open conformations for the different Plasmodium sequences. Then SANCDB compounds were screened to identify new potential DXR inhibitors with new chemical scaffolds. Finally, the identified hits were submitted to molecular dynamics studies, preceded by a parameterization of the manganese atom in the protein active site.
- Full Text:
- Date Issued: 2018
Studies towards the development of novel antimalarial agents
- Authors: Adeyemi, Christiana Modupe
- Date: 2015
- Subjects: Antimalarials , Malaria , Drug resistance , Drug development , Enzyme inhibitors , Plasmodium
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/54645 , vital:26596
- Description: Considerable efforts have been made in the modification of existing antimalarial drugs, and the support of incentive programmes have led to a drastic decrease in malaria cases reported by WHO during the past 6 years. However, the development of drug resistance threatens the eradication of this deadly disease and has prompted research on the synthesis of novel antimalarial drugs. Our research has involved the design and synthesis of novel benzylated phosphonate esters as potential 1-deoxy-D-xylose-5-phosphate reductoisomerase (DXR) inhibitors. A series of amidoalkylphosphonate esters were obtained by reacting various 3-subsituted anilines and heterocyclic amines with chloroalkanoyl chlorides and reacting the resulting chloroalkanamides with triethyl phosphite using Michaelis-Arbuzov methodology. Benzylation of the phosphonate esters afforded a series of novel N-benzylated derivatives in good yields and these compounds were fully characterised by NMR and HRMS methods. Several approaches to the introduction of a benzyl group at the C-2 position of the phosphonate ester derivatives have been explored, leading unexpectedly to the isolation of unprecedented tetrahydrofuranyl derivatives. Studies towards the preparation of potential bi-functional PfDXR / HIV-1 RT inhibitors have also been initiated. Preliminary in silico docking studies of selected non-benzylated and benzylated phosphonated derivatives into the Pf-DXR active-site has provided useful insight into the binding potential of these ligands. Bioassays have revealed a very low toxicity for all the synthesised phosphonated compounds and a number of these ligands also exhibit a promising inhibitory activity against the Plasmodium parasite.
- Full Text:
- Date Issued: 2015
- Authors: Adeyemi, Christiana Modupe
- Date: 2015
- Subjects: Antimalarials , Malaria , Drug resistance , Drug development , Enzyme inhibitors , Plasmodium
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/54645 , vital:26596
- Description: Considerable efforts have been made in the modification of existing antimalarial drugs, and the support of incentive programmes have led to a drastic decrease in malaria cases reported by WHO during the past 6 years. However, the development of drug resistance threatens the eradication of this deadly disease and has prompted research on the synthesis of novel antimalarial drugs. Our research has involved the design and synthesis of novel benzylated phosphonate esters as potential 1-deoxy-D-xylose-5-phosphate reductoisomerase (DXR) inhibitors. A series of amidoalkylphosphonate esters were obtained by reacting various 3-subsituted anilines and heterocyclic amines with chloroalkanoyl chlorides and reacting the resulting chloroalkanamides with triethyl phosphite using Michaelis-Arbuzov methodology. Benzylation of the phosphonate esters afforded a series of novel N-benzylated derivatives in good yields and these compounds were fully characterised by NMR and HRMS methods. Several approaches to the introduction of a benzyl group at the C-2 position of the phosphonate ester derivatives have been explored, leading unexpectedly to the isolation of unprecedented tetrahydrofuranyl derivatives. Studies towards the preparation of potential bi-functional PfDXR / HIV-1 RT inhibitors have also been initiated. Preliminary in silico docking studies of selected non-benzylated and benzylated phosphonated derivatives into the Pf-DXR active-site has provided useful insight into the binding potential of these ligands. Bioassays have revealed a very low toxicity for all the synthesised phosphonated compounds and a number of these ligands also exhibit a promising inhibitory activity against the Plasmodium parasite.
- Full Text:
- Date Issued: 2015
- «
- ‹
- 1
- ›
- »