AMBER force field parameters for the Zn (II) ions of the tunneling-fold enzymes GTP cyclohydrolase I and 6-pyruvoyl tetrahydropterin synthase:
- Khairallah, Afrah, Tastan Bishop, Özlem, Moses, Vuyani
- Authors: Khairallah, Afrah , Tastan Bishop, Özlem , Moses, Vuyani
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163068 , vital:41009 , DOI: 10.1080/07391102.2020.1796800
- Description: The folate biosynthesis pathway is an essential pathway for cell growth and survival. Folate derivatives serve as a source of the one-carbon units in several intracellular metabolic reactions. Rapidly dividing cells rely heavily on the availability of folate derivatives for their proliferation. As a result, drugs targeting this pathway have shown to be effective against tumor cells and pathogens, but drug resistance against the available antifolate drugs emerged quickly. Therefore, there is a need to develop new treatment strategies and identify alternative metabolic targets. The two de novo folate biosynthesis pathway enzymes, GTP cyclohydrolase I (GCH1) and 6-pyruvoyl tetrahydropterin synthase (PTPS), can provide an alternative strategy to overcome the drug resistance that emerged in the two primary targeted enzymes dihydrofolate reductase and dihydropteroate synthase.
- Full Text:
- Authors: Khairallah, Afrah , Tastan Bishop, Özlem , Moses, Vuyani
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163068 , vital:41009 , DOI: 10.1080/07391102.2020.1796800
- Description: The folate biosynthesis pathway is an essential pathway for cell growth and survival. Folate derivatives serve as a source of the one-carbon units in several intracellular metabolic reactions. Rapidly dividing cells rely heavily on the availability of folate derivatives for their proliferation. As a result, drugs targeting this pathway have shown to be effective against tumor cells and pathogens, but drug resistance against the available antifolate drugs emerged quickly. Therefore, there is a need to develop new treatment strategies and identify alternative metabolic targets. The two de novo folate biosynthesis pathway enzymes, GTP cyclohydrolase I (GCH1) and 6-pyruvoyl tetrahydropterin synthase (PTPS), can provide an alternative strategy to overcome the drug resistance that emerged in the two primary targeted enzymes dihydrofolate reductase and dihydropteroate synthase.
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Characterisation of plasmodial transketolases and identification of potential inhibitors: an in silico study
- Boateng, Rita A, Tastan Bishop, Özlem, Musyoka, Thommas M
- Authors: Boateng, Rita A , Tastan Bishop, Özlem , Musyoka, Thommas M
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/429372 , vital:72605 , xlink:href="https://doi.org/10.1186/s12936-020-03512-1"
- Description: Plasmodial transketolase (PTKT) enzyme is one of the novel pharmacological targets being explored as potential anti-malarial drug target due to its functional role and low sequence identity to the human enzyme. Despite this, features contributing to such have not been exploited for anti-malarial drug design. Additionally, there are no anti-malarial drugs targeting PTKTs whereas the broad activity of these inhibitors against PTKTs from other Plasmodium spp. is yet to be reported. This study characterises different PTKTs [Plasmodium falciparum (PfTKT), Plasmodium vivax (PvTKT), Plasmodium ovale (PoTKT), Plasmodium malariae (PmTKT) and Plasmodium knowlesi (PkTKT) and the human homolog (HsTKT)] to identify key sequence and structural based differences as well as the identification of selective potential inhibitors against PTKTs.
- Full Text:
- Authors: Boateng, Rita A , Tastan Bishop, Özlem , Musyoka, Thommas M
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/429372 , vital:72605 , xlink:href="https://doi.org/10.1186/s12936-020-03512-1"
- Description: Plasmodial transketolase (PTKT) enzyme is one of the novel pharmacological targets being explored as potential anti-malarial drug target due to its functional role and low sequence identity to the human enzyme. Despite this, features contributing to such have not been exploited for anti-malarial drug design. Additionally, there are no anti-malarial drugs targeting PTKTs whereas the broad activity of these inhibitors against PTKTs from other Plasmodium spp. is yet to be reported. This study characterises different PTKTs [Plasmodium falciparum (PfTKT), Plasmodium vivax (PvTKT), Plasmodium ovale (PoTKT), Plasmodium malariae (PmTKT) and Plasmodium knowlesi (PkTKT) and the human homolog (HsTKT)] to identify key sequence and structural based differences as well as the identification of selective potential inhibitors against PTKTs.
- Full Text:
Determining the unbinding events and conserved motions associated with the pyrazinamide release due to resistance mutations of Mycobacterium tuberculosis pyrazinamidase:
- Amamuddy, Olivier S, Musyoka, Thommas M, Boateng, Rita A, Zabo, Sophakama, Tastan Bishop, Özlem
- Authors: Amamuddy, Olivier S , Musyoka, Thommas M , Boateng, Rita A , Zabo, Sophakama , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148869 , vital:38781 , https://doi.org/10.1016/j.csbj.2020.05.0099
- Description: Pyrazinamide (PZA) is the only first-line antitubercular drug active against latent Mycobacterium tuberculosis (Mtb). It is activated to pyrazinoic acid by the pncA-encoded pyrazinamidase enzyme (PZase). Despite the emergence of PZA drug resistance, the underlying mechanisms of resistance remain unclear. This study investigated part of these mechanisms by modelling a PZA-bound wild type and 82 mutant PZase structures before applying molecular dynamics (MD) with an accurate Fe2+ cofactor coordination geometry.
- Full Text:
- Authors: Amamuddy, Olivier S , Musyoka, Thommas M , Boateng, Rita A , Zabo, Sophakama , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148869 , vital:38781 , https://doi.org/10.1016/j.csbj.2020.05.0099
- Description: Pyrazinamide (PZA) is the only first-line antitubercular drug active against latent Mycobacterium tuberculosis (Mtb). It is activated to pyrazinoic acid by the pncA-encoded pyrazinamidase enzyme (PZase). Despite the emergence of PZA drug resistance, the underlying mechanisms of resistance remain unclear. This study investigated part of these mechanisms by modelling a PZA-bound wild type and 82 mutant PZase structures before applying molecular dynamics (MD) with an accurate Fe2+ cofactor coordination geometry.
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Identification of Selective Novel Hits against Plasmodium falciparum Prolyl tRNA Synthetase Active Site and a Predicted Allosteric Site Using in silico Approaches:
- Nyamai, Dorothy Wavinya, Tastan Bishop, Özlem
- Authors: Nyamai, Dorothy Wavinya , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149229 , vital:38817 , https://doi.org/10.3390/ijms21113803
- Description: Recently, there has been increased interest in aminoacyl tRNA synthetases (aaRSs) as potential malarial drug targets. These enzymes play a key role in protein translation by the addition of amino acids to their cognate tRNA. The aaRSs are present in all Plasmodium life cycle stages, and thus present an attractive malarial drug target. Prolyl tRNA synthetase is a class II aaRS that functions in charging tRNA with proline. Various inhibitors against Plasmodium falciparum ProRS (PfProRS) active site have been designed. However, none have gone through clinical trials as they have been found to be highly toxic to human cells. Recently, a possible allosteric site was reported in PfProRS with two possible allosteric modulators: glyburide and TCMDC-124506. In this study, we sought to identify novel selective inhibitors targeting PfProRS active site and possible novel allosteric modulators of this enzyme. To achieve this, virtual screening of South African natural compounds against PfProRS and the human homologue was carried out using AutoDock Vina. The modulation of protein motions by ligand binding was studied by molecular dynamics (MD) using the GROningen MAchine for Chemical Simulations (GROMACS) tool. To further analyse the protein global motions and energetic changes upon ligand binding, principal component analysis (PCA), and free energy landscape (FEL) calculations were performed.
- Full Text:
- Authors: Nyamai, Dorothy Wavinya , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149229 , vital:38817 , https://doi.org/10.3390/ijms21113803
- Description: Recently, there has been increased interest in aminoacyl tRNA synthetases (aaRSs) as potential malarial drug targets. These enzymes play a key role in protein translation by the addition of amino acids to their cognate tRNA. The aaRSs are present in all Plasmodium life cycle stages, and thus present an attractive malarial drug target. Prolyl tRNA synthetase is a class II aaRS that functions in charging tRNA with proline. Various inhibitors against Plasmodium falciparum ProRS (PfProRS) active site have been designed. However, none have gone through clinical trials as they have been found to be highly toxic to human cells. Recently, a possible allosteric site was reported in PfProRS with two possible allosteric modulators: glyburide and TCMDC-124506. In this study, we sought to identify novel selective inhibitors targeting PfProRS active site and possible novel allosteric modulators of this enzyme. To achieve this, virtual screening of South African natural compounds against PfProRS and the human homologue was carried out using AutoDock Vina. The modulation of protein motions by ligand binding was studied by molecular dynamics (MD) using the GROningen MAchine for Chemical Simulations (GROMACS) tool. To further analyse the protein global motions and energetic changes upon ligand binding, principal component analysis (PCA), and free energy landscape (FEL) calculations were performed.
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Impact of early pandemic stage mutations on molecular dynamics of SARS-CoV-2 Mpro:
- Amamuddy, Olivier S, Verkhivker, Gennady M, Tastan Bishop, Özlem
- Authors: Amamuddy, Olivier S , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162330 , vital:40835 , https://0-doi.org.wam.seals.ac.za/10.1021/acs.jcim.0c00634
- Description: A new coronavirus (SARS-CoV-2) is a global threat to world health and economy. Its dimeric main protease (Mpro), which is required for the proteolytic cleavage of viral precursor proteins, is a good candidate for drug development owing to its conservation and the absence of a human homolog. Improving our understanding of Mpro behavior can accelerate the discovery of effective therapies to reduce mortality. All-atom molecular dynamics (MD) simulations (100 ns) of 50 mutant Mpro dimers obtained from filtered sequences from the GISAID database were analyzed using root-mean-square deviation, root-mean-square fluctuation, Rg, averaged betweenness centrality, and geometry calculations.
- Full Text:
- Authors: Amamuddy, Olivier S , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162330 , vital:40835 , https://0-doi.org.wam.seals.ac.za/10.1021/acs.jcim.0c00634
- Description: A new coronavirus (SARS-CoV-2) is a global threat to world health and economy. Its dimeric main protease (Mpro), which is required for the proteolytic cleavage of viral precursor proteins, is a good candidate for drug development owing to its conservation and the absence of a human homolog. Improving our understanding of Mpro behavior can accelerate the discovery of effective therapies to reduce mortality. All-atom molecular dynamics (MD) simulations (100 ns) of 50 mutant Mpro dimers obtained from filtered sequences from the GISAID database were analyzed using root-mean-square deviation, root-mean-square fluctuation, Rg, averaged betweenness centrality, and geometry calculations.
- Full Text:
Impact of emerging mutations on the dynamic properties the SARS-CoV-2 main protease: an in silico investigation
- Amamuddy, Olivier S, Verkhivker, Gennady M, Tastan Bishop, Özlem
- Authors: Amamuddy, Olivier S , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163035 , vital:41006 , doi: 10.1021/acs.jcim.0c00634
- Description: The new coronavirus (SARS-CoV-2) is a global threat to world health and its economy. Its main protease (Mpro), which functions as a dimer, cleaves viral precursor proteins in the process of viral maturation. It is a good candidate for drug development owing to its conservation and the absence of a human homolog. An improved understanding of the protein behaviour can accelerate the discovery of effective therapies in order to reduce mortality. 100 ns all-atom molecular dynamics simulations of 50 homology modelled mutant Mpro dimers were performed at pH 7 from filtered sequences obtained from the GISAID database. Protease dynamics were analysed using RMSD, RMSF, Rg, the averaged betweenness centrality and geometry calculations. Domains from each Mpro protomer were found to generally have independent motions, while the dimer-stabilising N-finger region was found to be flexible in most mutants.
- Full Text:
- Authors: Amamuddy, Olivier S , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163035 , vital:41006 , doi: 10.1021/acs.jcim.0c00634
- Description: The new coronavirus (SARS-CoV-2) is a global threat to world health and its economy. Its main protease (Mpro), which functions as a dimer, cleaves viral precursor proteins in the process of viral maturation. It is a good candidate for drug development owing to its conservation and the absence of a human homolog. An improved understanding of the protein behaviour can accelerate the discovery of effective therapies in order to reduce mortality. 100 ns all-atom molecular dynamics simulations of 50 homology modelled mutant Mpro dimers were performed at pH 7 from filtered sequences obtained from the GISAID database. Protease dynamics were analysed using RMSD, RMSF, Rg, the averaged betweenness centrality and geometry calculations. Domains from each Mpro protomer were found to generally have independent motions, while the dimer-stabilising N-finger region was found to be flexible in most mutants.
- Full Text:
Integrated computational approaches and tools for allosteric drug discovery:
- Amamuddy, Olivier S, Veldman, Wade, Manyumwa, Colleen, Khairallah, Afrah, Agajanian, Steve, Oluyemi, Odeyemi, Verkhivker, Gennady M, Tastan Bishop, Özlem
- Authors: Amamuddy, Olivier S , Veldman, Wade , Manyumwa, Colleen , Khairallah, Afrah , Agajanian, Steve , Oluyemi, Odeyemi , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163012 , vital:41004 , https://doi.org/10.3390/ijms21030847
- Description: Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. As such, the critical analysis and integration of established approaches into robust, reproducible, and customizable computational pipelines with experimental feedback could make allosteric drug discovery more efficient and reliable. In this article, we review computational approaches for allosteric drug discovery and discuss how these tools can be utilized to develop consensus workflows for in silico identification of allosteric sites and modulators with some applications to pathogen resistance and precision medicine. The emerging realization that allosteric modulators can exploit distinct regulatory mechanisms and can provide access to targeted modulation of protein activities could open opportunities for probing biological processes and in silico design of drug combinations with improved therapeutic indices and a broad range of activities.
- Full Text:
- Authors: Amamuddy, Olivier S , Veldman, Wade , Manyumwa, Colleen , Khairallah, Afrah , Agajanian, Steve , Oluyemi, Odeyemi , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163012 , vital:41004 , https://doi.org/10.3390/ijms21030847
- Description: Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. As such, the critical analysis and integration of established approaches into robust, reproducible, and customizable computational pipelines with experimental feedback could make allosteric drug discovery more efficient and reliable. In this article, we review computational approaches for allosteric drug discovery and discuss how these tools can be utilized to develop consensus workflows for in silico identification of allosteric sites and modulators with some applications to pathogen resistance and precision medicine. The emerging realization that allosteric modulators can exploit distinct regulatory mechanisms and can provide access to targeted modulation of protein activities could open opportunities for probing biological processes and in silico design of drug combinations with improved therapeutic indices and a broad range of activities.
- Full Text:
Probing the structural dynamics of the Plasmodium falciparum tunneling-fold enzyme 6-pyruvoyl tetrahydropterin synthase to reveal allosteric drug targeting sites:
- Khairallah, Afrah, Ross, Caroline J, Tastan Bishop, Özlem
- Authors: Khairallah, Afrah , Ross, Caroline J , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163057 , vital:41008 , https://doi.org/10.3389/fmolb.2020.575196
- Description: The de novo folate synthesis pathway is a well-established drug target in the treatment of many infectious diseases. Antimalarial antifolate drugs have proven to be effective against malaria, however, rapid drug resistance has emerged on the two primary targeted enzymes: dihydrofolate reductase and dihydroptoreate synthase. The need to identify alternative antifolate drugs and novel metabolic targets is of imminent importance. The 6-pyruvol tetrahydropterin synthase (PTPS) enzyme belongs to the tunneling fold protein superfamily which is characterized by a distinct central tunnel/cavity. The enzyme catalyzes the second reaction step of the parasite’s de novo folate synthesis pathway and is responsible for the conversion of 7,8-dihydroneopterin to 6-pyruvoyl-tetrahydropterin. In this study, we examine the structural dynamics of Plasmodium falciparum PTPS using the anisotropic network model, to elucidate the collective motions that drive the function of the enzyme and identify potential sites for allosteric modulation of its binding properties.
- Full Text:
- Authors: Khairallah, Afrah , Ross, Caroline J , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163057 , vital:41008 , https://doi.org/10.3389/fmolb.2020.575196
- Description: The de novo folate synthesis pathway is a well-established drug target in the treatment of many infectious diseases. Antimalarial antifolate drugs have proven to be effective against malaria, however, rapid drug resistance has emerged on the two primary targeted enzymes: dihydrofolate reductase and dihydroptoreate synthase. The need to identify alternative antifolate drugs and novel metabolic targets is of imminent importance. The 6-pyruvol tetrahydropterin synthase (PTPS) enzyme belongs to the tunneling fold protein superfamily which is characterized by a distinct central tunnel/cavity. The enzyme catalyzes the second reaction step of the parasite’s de novo folate synthesis pathway and is responsible for the conversion of 7,8-dihydroneopterin to 6-pyruvoyl-tetrahydropterin. In this study, we examine the structural dynamics of Plasmodium falciparum PTPS using the anisotropic network model, to elucidate the collective motions that drive the function of the enzyme and identify potential sites for allosteric modulation of its binding properties.
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Structural Characterization of Carbonic Anhydrase VIII and Effects of Missense Single Nucleotide Variations to Protein Structure and Function:
- Sanyanga, Taremekedzwa Allan, Tastan Bishop, Özlem
- Authors: Sanyanga, Taremekedzwa Allan , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149670 , vital:38873 , https://doi.org/10.3390/ijms21082764
- Description: Human carbonic anhydrase 8 (CA-VIII) is an acatalytic isoform of the α -CA family. Though the protein cannot hydrate CO2, CA-VIII is essential for calcium (Ca2+) homeostasis within the body, and achieves this by allosterically inhibiting the binding of inositol 1,4,5-triphosphate (IP3) to the IP3 receptor type 1 (ITPR1) protein. However, the mechanism of interaction of CA-VIII to ITPR1 is not well understood. In addition, functional defects to CA-VIII due to non-synonymous single nucleotide polymorphisms (nsSNVs) result in Ca2+ dysregulation and the development of the phenotypes such as cerebellar ataxia, mental retardation and disequilibrium syndrome 3 (CAMRQ3). The pathogenesis of CAMRQ3 is also not well understood. The structure and function of CA-VIII was characterised, and pathogenesis of CAMRQ3 investigated. Structural and functional characterisation of CA-VIII was conducted through SiteMap and CPORT to identify potential binding site residues.
- Full Text:
- Authors: Sanyanga, Taremekedzwa Allan , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149670 , vital:38873 , https://doi.org/10.3390/ijms21082764
- Description: Human carbonic anhydrase 8 (CA-VIII) is an acatalytic isoform of the α -CA family. Though the protein cannot hydrate CO2, CA-VIII is essential for calcium (Ca2+) homeostasis within the body, and achieves this by allosterically inhibiting the binding of inositol 1,4,5-triphosphate (IP3) to the IP3 receptor type 1 (ITPR1) protein. However, the mechanism of interaction of CA-VIII to ITPR1 is not well understood. In addition, functional defects to CA-VIII due to non-synonymous single nucleotide polymorphisms (nsSNVs) result in Ca2+ dysregulation and the development of the phenotypes such as cerebellar ataxia, mental retardation and disequilibrium syndrome 3 (CAMRQ3). The pathogenesis of CAMRQ3 is also not well understood. The structure and function of CA-VIII was characterised, and pathogenesis of CAMRQ3 investigated. Structural and functional characterisation of CA-VIII was conducted through SiteMap and CPORT to identify potential binding site residues.
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The In Silico Prediction of hotspot residues that contribute to the structural stability of subunit interfaces of a Picornavirus Capsid:
- Upfold, Nicole, Ross, Caroline J, Tastan Bishop, Özlem, Knox, Caroline M
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Knox, Caroline M
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149970 , vital:38919 , https://doi.org/10.3390/v12040387
- Description: The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot residues at the intraprotomer, interprotomer and interpentamer interfaces of the Theiler’s murine encephalomyelitis virus (TMEV) capsid.
- Full Text:
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Knox, Caroline M
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149970 , vital:38919 , https://doi.org/10.3390/v12040387
- Description: The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot residues at the intraprotomer, interprotomer and interpentamer interfaces of the Theiler’s murine encephalomyelitis virus (TMEV) capsid.
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Understanding the Pyrimethamine drug resistance mechanism via combined molecular dynamics and dynamic residue network analysis:
- Amusengeri, Arnold, Tata, Rolland B, Tastan Bishop, Özlem
- Authors: Amusengeri, Arnold , Tata, Rolland B , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163022 , vital:41005 , https://doi.org/10.3390/molecules25040904
- Description: In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity.
- Full Text:
- Authors: Amusengeri, Arnold , Tata, Rolland B , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163022 , vital:41005 , https://doi.org/10.3390/molecules25040904
- Description: In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity.
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