JMS: a workflow management system and web-based cluster front-end for the Torque resource manager
- Brown, David K, Musyoka, Thommas M, Penkler, David L, Tastan Bishop, Özlem
- Authors: Brown, David K , Musyoka, Thommas M , Penkler, David L , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148049 , vital:38705 , https://arxiv.org/abs/1501.06907
- Description: Complex computational pipelines are becoming a staple of modern scientific research. Often these pipelines are resource intensive and require days of computing time. In such cases, it makes sense to run them over distributed computer clusters where they can take advantage of the aggregated resources of many powerful computers. In addition to this, researchers often want to integrate their workflows into their own web servers. In these cases, software is needed to manage the submission of jobs from the web interface to the cluster and then return the results once the job has finished executing.
- Full Text:
- Date Issued: 2015
- Authors: Brown, David K , Musyoka, Thommas M , Penkler, David L , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148049 , vital:38705 , https://arxiv.org/abs/1501.06907
- Description: Complex computational pipelines are becoming a staple of modern scientific research. Often these pipelines are resource intensive and require days of computing time. In such cases, it makes sense to run them over distributed computer clusters where they can take advantage of the aggregated resources of many powerful computers. In addition to this, researchers often want to integrate their workflows into their own web servers. In these cases, software is needed to manage the submission of jobs from the web interface to the cluster and then return the results once the job has finished executing.
- Full Text:
- Date Issued: 2015
Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: combined study of molecular modeling and dynamic residue network analysis
- Amusengeri, Arnold, Tastan Bishop, Özlem
- Authors: Amusengeri, Arnold , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162949 , vital:40999 , https://doi.org/10.3390/molecules24010188
- Description: The human heat shock proteins (Hsps), predominantly Hsp72 and Hsp90, have been strongly implicated in various critical stages of oncogenesis and progression of human cancers. While drug development has extensively focused on Hsp90 as a potential anticancer target, much less effort has been put against Hsp72. This work investigated the therapeutic potential of Hsp72 and its constitutive isoform, Hsc70, via in silico-based screening against the South African Natural Compounds Database (SANCDB). A comparative modeling approach was used to obtain nearly full-length 3D structures of the closed conformation of Hsp72 and Hsc70 proteins. Molecular docking of SANCDB compounds identified one potential allosteric modulator, Discorhabdin N, binding to the allosteric β substrate binding domain (SBDβ) back pocket, with good binding affinities in both cases.
- Full Text:
- Date Issued: 2019
- Authors: Amusengeri, Arnold , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162949 , vital:40999 , https://doi.org/10.3390/molecules24010188
- Description: The human heat shock proteins (Hsps), predominantly Hsp72 and Hsp90, have been strongly implicated in various critical stages of oncogenesis and progression of human cancers. While drug development has extensively focused on Hsp90 as a potential anticancer target, much less effort has been put against Hsp72. This work investigated the therapeutic potential of Hsp72 and its constitutive isoform, Hsc70, via in silico-based screening against the South African Natural Compounds Database (SANCDB). A comparative modeling approach was used to obtain nearly full-length 3D structures of the closed conformation of Hsp72 and Hsc70 proteins. Molecular docking of SANCDB compounds identified one potential allosteric modulator, Discorhabdin N, binding to the allosteric β substrate binding domain (SBDβ) back pocket, with good binding affinities in both cases.
- Full Text:
- Date Issued: 2019
No evidence for association between APOL1 kidney disease risk alleles and Human African Trypanosomiasis in two Ugandan populations:
- Kimuda, Magambo P, Noyes, Harry, Mulindwa, Julius, Enyaru, John, Alibu, Vincent P, Sidibe, Issa, Mumba Ngoyi, Dieuodonne, Hertz-Fowler, Christiane, MacLeod, Annette, Tastan Bishop, Özlem, Matovu, Enock
- Authors: Kimuda, Magambo P , Noyes, Harry , Mulindwa, Julius , Enyaru, John , Alibu, Vincent P , Sidibe, Issa , Mumba Ngoyi, Dieuodonne , Hertz-Fowler, Christiane , MacLeod, Annette , Tastan Bishop, Özlem , Matovu, Enock
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162924 , vital:40997 , https://doi.org/10.1371/journal.pntd.0006300
- Description: Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT.
- Full Text:
- Date Issued: 2018
- Authors: Kimuda, Magambo P , Noyes, Harry , Mulindwa, Julius , Enyaru, John , Alibu, Vincent P , Sidibe, Issa , Mumba Ngoyi, Dieuodonne , Hertz-Fowler, Christiane , MacLeod, Annette , Tastan Bishop, Özlem , Matovu, Enock
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162924 , vital:40997 , https://doi.org/10.1371/journal.pntd.0006300
- Description: Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT.
- Full Text:
- Date Issued: 2018
How to establish a bioinformatics postgraduate degree programme—a case study from South Africa
- Machanick, Philip, Tastan Bishop, Özlem
- Authors: Machanick, Philip , Tastan Bishop, Özlem
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124641 , vital:35641 , https://doi.10.1093/bib/bbu014
- Description: The Research Unit in Bioinformatics at Rhodes University (RUBi), South Africa, offers a Masters of Science in Bioinformatics.Growing demand for bioinformatics qualifications results in applications from across Africa.Courses aim to bridge gaps in the diverse backgrounds of students who range from biologists with no prior computing exposure to computer scientists with no biology background. The programme is evenly split between coursework and research, with diverse modules from a range of departments coveringmathematics, statistics, computer science and biology, with emphasis on application to bioinformatics research. The early focus on research helps bring students up to speed with working as a researcher. We measure success of the programme by the high rate of subsequent entry to PhD study: 10 of 14 students who completed in the years 2011-2013.
- Full Text:
- Date Issued: 2014
- Authors: Machanick, Philip , Tastan Bishop, Özlem
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124641 , vital:35641 , https://doi.10.1093/bib/bbu014
- Description: The Research Unit in Bioinformatics at Rhodes University (RUBi), South Africa, offers a Masters of Science in Bioinformatics.Growing demand for bioinformatics qualifications results in applications from across Africa.Courses aim to bridge gaps in the diverse backgrounds of students who range from biologists with no prior computing exposure to computer scientists with no biology background. The programme is evenly split between coursework and research, with diverse modules from a range of departments coveringmathematics, statistics, computer science and biology, with emphasis on application to bioinformatics research. The early focus on research helps bring students up to speed with working as a researcher. We measure success of the programme by the high rate of subsequent entry to PhD study: 10 of 14 students who completed in the years 2011-2013.
- Full Text:
- Date Issued: 2014
Study of protein complexes via homology modeling, applied to cysteine proteases and their protein inhibitors:
- Tastan Bishop, Özlem, Kroon, Matthys
- Authors: Tastan Bishop, Özlem , Kroon, Matthys
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148070 , vital:38707 , DOI: 10.1007/s00894-011-0990-y
- Description: This paper develops and evaluates large-scale calculation of 3D structures of protein complexes by homology modeling as a promising new approach for protein docking. The complexes investigated were papain-like cysteine proteases and their protein inhibitors, which play numerous roles in human and parasitic metabolisms. The structural modeling was performed in two parts. For the first part (evaluation set), nine crystal structure complexes were selected, 1325 homology models of known complexes were rebuilt by various templates including hybrids, allowing an analysis of the factors influencing the accuracy of the models. The important considerations for modeling the interface were protease coverage and inhibitor sequence identity. In the second part (study set), the findings of the evaluation set were used to select appropriate templates to model novel cysteine protease-inhibitor complexes from human and malaria parasites Plasmodium falciparum and Plasmodium vivax. The energy scores, considering the evaluation set, indicate that the models are of high accuracy.
- Full Text:
- Date Issued: 2011
- Authors: Tastan Bishop, Özlem , Kroon, Matthys
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148070 , vital:38707 , DOI: 10.1007/s00894-011-0990-y
- Description: This paper develops and evaluates large-scale calculation of 3D structures of protein complexes by homology modeling as a promising new approach for protein docking. The complexes investigated were papain-like cysteine proteases and their protein inhibitors, which play numerous roles in human and parasitic metabolisms. The structural modeling was performed in two parts. For the first part (evaluation set), nine crystal structure complexes were selected, 1325 homology models of known complexes were rebuilt by various templates including hybrids, allowing an analysis of the factors influencing the accuracy of the models. The important considerations for modeling the interface were protease coverage and inhibitor sequence identity. In the second part (study set), the findings of the evaluation set were used to select appropriate templates to model novel cysteine protease-inhibitor complexes from human and malaria parasites Plasmodium falciparum and Plasmodium vivax. The energy scores, considering the evaluation set, indicate that the models are of high accuracy.
- Full Text:
- Date Issued: 2011
Novel potential antimalarials through drug repurposing and multitargeting: a Computational Approach
- Diallo, Bakary N, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162676 , vital:40972 , https://doi.org/10.21955/aasopenres.1114955.1
- Description: This study aims to identify potential antimalarials from Food and Drug Administration (FDA) approved drugs.
- Full Text:
- Date Issued: 2019
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162676 , vital:40972 , https://doi.org/10.21955/aasopenres.1114955.1
- Description: This study aims to identify potential antimalarials from Food and Drug Administration (FDA) approved drugs.
- Full Text:
- Date Issued: 2019
Development of Bioinformatics Infrastructure for Genomics Research:
- Mulder, Nicola J, Adebiyi, Ezekiel, Adebiyi, Marion, Adeyemi, Seun, Ahmed, Azza, Ahmed, Rehab, Akanle, Bola, Alibi, Mohamed, Armstrong, Don L, Aron, Shaun, Ashano, Efejiro, Baichoo, Shakuntala, Benkahla, Alia, Brown, David K, Chimusa, Emile Rugamika, Fadlelmola, Faisal M, Falola, Dare, Fatumo, Segun, Ghedira, Kais, Ghouila, Amel, Hazelhurst, Scott, Itunuoluwa Isewon, Segun Jung, Kassim, Samar Kamal, Kayondo, Jonathan K, Mbiyavanga, Mamana, Meintjes, Ayton, Mohammed, Somia, Mosaku, Abayomi, Moussa, Ahmed, Muhammd, Mustafa, Mungloo-Dilmohamud, Zahra, Nashiru, Oyekanmi, Odia, Trust, Okafor, Adaobi, Oladipo, Olaleye, Osamor, Victor, Oyelade, Jellili, Sadki, Khalid, Salifu, Samson Pandam, Soyemi, Jumoke, Panji, Sumir, Radouani, Fouzia, Souiai, Oussama, Tastan Bishop, Özlem
- Authors: Mulder, Nicola J , Adebiyi, Ezekiel , Adebiyi, Marion , Adeyemi, Seun , Ahmed, Azza , Ahmed, Rehab , Akanle, Bola , Alibi, Mohamed , Armstrong, Don L , Aron, Shaun , Ashano, Efejiro , Baichoo, Shakuntala , Benkahla, Alia , Brown, David K , Chimusa, Emile Rugamika , Fadlelmola, Faisal M , Falola, Dare , Fatumo, Segun , Ghedira, Kais , Ghouila, Amel , Hazelhurst, Scott , Itunuoluwa Isewon , Segun Jung , Kassim, Samar Kamal , Kayondo, Jonathan K , Mbiyavanga, Mamana , Meintjes, Ayton , Mohammed, Somia , Mosaku, Abayomi , Moussa, Ahmed , Muhammd, Mustafa , Mungloo-Dilmohamud, Zahra , Nashiru, Oyekanmi , Odia, Trust , Okafor, Adaobi , Oladipo, Olaleye , Osamor, Victor , Oyelade, Jellili , Sadki, Khalid , Salifu, Samson Pandam , Soyemi, Jumoke , Panji, Sumir , Radouani, Fouzia , Souiai, Oussama , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148239 , vital:38722 , DOI: 10.1016/j.gheart.2017.01.005
- Description: Although pockets of bioinformatics excellence have developed in Africa, generally, large-scale genomic data analysis has been limited by the availability of expertise and infrastructure. H3ABioNet, a pan-African bioinformatics network, was established to build capacity specifically to enable H3Africa (Human Heredity and Health in Africa) researchers to analyze their data in Africa. Since the inception of the H3Africa initiative, H3ABioNet's role has evolved in response to changing needs from the consortium and the African bioinformatics community.
- Full Text:
- Date Issued: 2017
- Authors: Mulder, Nicola J , Adebiyi, Ezekiel , Adebiyi, Marion , Adeyemi, Seun , Ahmed, Azza , Ahmed, Rehab , Akanle, Bola , Alibi, Mohamed , Armstrong, Don L , Aron, Shaun , Ashano, Efejiro , Baichoo, Shakuntala , Benkahla, Alia , Brown, David K , Chimusa, Emile Rugamika , Fadlelmola, Faisal M , Falola, Dare , Fatumo, Segun , Ghedira, Kais , Ghouila, Amel , Hazelhurst, Scott , Itunuoluwa Isewon , Segun Jung , Kassim, Samar Kamal , Kayondo, Jonathan K , Mbiyavanga, Mamana , Meintjes, Ayton , Mohammed, Somia , Mosaku, Abayomi , Moussa, Ahmed , Muhammd, Mustafa , Mungloo-Dilmohamud, Zahra , Nashiru, Oyekanmi , Odia, Trust , Okafor, Adaobi , Oladipo, Olaleye , Osamor, Victor , Oyelade, Jellili , Sadki, Khalid , Salifu, Samson Pandam , Soyemi, Jumoke , Panji, Sumir , Radouani, Fouzia , Souiai, Oussama , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148239 , vital:38722 , DOI: 10.1016/j.gheart.2017.01.005
- Description: Although pockets of bioinformatics excellence have developed in Africa, generally, large-scale genomic data analysis has been limited by the availability of expertise and infrastructure. H3ABioNet, a pan-African bioinformatics network, was established to build capacity specifically to enable H3Africa (Human Heredity and Health in Africa) researchers to analyze their data in Africa. Since the inception of the H3Africa initiative, H3ABioNet's role has evolved in response to changing needs from the consortium and the African bioinformatics community.
- Full Text:
- Date Issued: 2017
Structure-based analysis of single nucleotide variants in the renin-angiotensinogen complex:
- Brown, David K, Olivier, Sheik Amamuddy, Tastan Bishop, Özlem
- Authors: Brown, David K , Olivier, Sheik Amamuddy , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/147994 , vital:38700 , https://doi.org/10.1016/j.gheart.2017.01.006
- Description: The renin-angiotensin system (RAS) plays an important role in regulating blood pressure and controlling sodium levels in the blood. Hyperactivity of this system has been linked to numerous conditions including hypertension, kidney disease, and congestive heart failure. Three classes of drugs have been developed to inhibit RAS. In this study, we provide a structure-based analysis of the effect of single nucleotide variants (SNVs) on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants for further inhibitor design purposes.
- Full Text:
- Date Issued: 2017
- Authors: Brown, David K , Olivier, Sheik Amamuddy , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/147994 , vital:38700 , https://doi.org/10.1016/j.gheart.2017.01.006
- Description: The renin-angiotensin system (RAS) plays an important role in regulating blood pressure and controlling sodium levels in the blood. Hyperactivity of this system has been linked to numerous conditions including hypertension, kidney disease, and congestive heart failure. Three classes of drugs have been developed to inhibit RAS. In this study, we provide a structure-based analysis of the effect of single nucleotide variants (SNVs) on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants for further inhibitor design purposes.
- Full Text:
- Date Issued: 2017
Plasmodium falciparum Hop: detailed analysis on complex formation with Hsp70 and Hsp90
- Hatherley, Rowan, Clitheroe, Crystal-Leigh, Faya, Ngonidzashe, Tastan Bishop, Özlem
- Authors: Hatherley, Rowan , Clitheroe, Crystal-Leigh , Faya, Ngonidzashe , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163532 , vital:41046 , https://doi.org/10.1016/j.bbrc.2014.11.103
- Description: The heat shock organizing protein (Hop) is important in modulating the activity and co-interaction of two chaperones: heat shock protein 70 and 90 (Hsp70 and Hsp90). Recent research suggested that Plasmodium falciparum Hop (PfHop), PfHsp70 and PfHsp90 form a complex in the trophozoite infective stage. However, there has been little computational research on the malarial Hop protein in complex with other malarial Hsps.
- Full Text:
- Date Issued: 2015
- Authors: Hatherley, Rowan , Clitheroe, Crystal-Leigh , Faya, Ngonidzashe , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163532 , vital:41046 , https://doi.org/10.1016/j.bbrc.2014.11.103
- Description: The heat shock organizing protein (Hop) is important in modulating the activity and co-interaction of two chaperones: heat shock protein 70 and 90 (Hsp70 and Hsp90). Recent research suggested that Plasmodium falciparum Hop (PfHop), PfHsp70 and PfHsp90 form a complex in the trophozoite infective stage. However, there has been little computational research on the malarial Hop protein in complex with other malarial Hsps.
- Full Text:
- Date Issued: 2015
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:
- Date Issued: 2020
- 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:
- Date Issued: 2020
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:
- Date Issued: 2020
- 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:
- Date Issued: 2020
The determination of CHARMM force field parameters for the Mg2+ containing HIV-1 integrase:
- Musyoka, Thommas, Tastan Bishop, Özlem, Lobb, Kevin A, Moses, Vuyani
- Authors: Musyoka, Thommas , Tastan Bishop, Özlem , Lobb, Kevin A , Moses, Vuyani
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148139 , vital:38713 , DOI: 10.1016/j.cplett.2018.09.019
- Description: The HIV integrase enzyme is a validated drug target. However, its potential has remained largely unexploited until recently due to lack of structural and mechanistic information. Its catalytic core domain (CCD) is crucial for the viral-human DNA integration making integrase an ideal target for inhibitor design. However, in order to do so, force field parameters for the integrase magnesium ion need to be established. Quantum mechanical calculations were used to derive force field parameters which were validated through molecular dynamics studies. Our results show that the parameters determined accurately maintain the integrity of the metal pocket of the integrase CCD.
- Full Text:
- Date Issued: 2018
- Authors: Musyoka, Thommas , Tastan Bishop, Özlem , Lobb, Kevin A , Moses, Vuyani
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148139 , vital:38713 , DOI: 10.1016/j.cplett.2018.09.019
- Description: The HIV integrase enzyme is a validated drug target. However, its potential has remained largely unexploited until recently due to lack of structural and mechanistic information. Its catalytic core domain (CCD) is crucial for the viral-human DNA integration making integrase an ideal target for inhibitor design. However, in order to do so, force field parameters for the integrase magnesium ion need to be established. Quantum mechanical calculations were used to derive force field parameters which were validated through molecular dynamics studies. Our results show that the parameters determined accurately maintain the integrity of the metal pocket of the integrase CCD.
- Full Text:
- Date Issued: 2018
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:
- Date Issued: 2020
- 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:
- Date Issued: 2020
PRIMO: an interactive homology modeling pipeline
- Hatherley, Rowan, Brown, David K, Glenister, Michael, Tastan Bishop, Özlem
- Authors: Hatherley, Rowan , Brown, David K , Glenister, Michael , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148282 , vital:38726 , doi: 10.1371/journal.pone.0166698
- Description: The development of automated servers to predict the three-dimensional structure of proteins has seen much progress over the years. These servers make calculations simpler, but largely exclude users from the process. In this study, we present the PRotein Interactive MOdeling (PRIMO) pipeline for homology modeling of protein monomers. The pipeline eases the multi-step modeling process, and reduces the workload required by the user, while still allowing engagement from the user during every step. Default parameters are given for each step, which can either be modified or supplemented with additional external input. PRIMO has been designed for users of varying levels of experience with homology modeling. The pipeline incorporates a user-friendly interface that makes it easy to alter parameters used during modeling.
- Full Text:
- Date Issued: 2017
- Authors: Hatherley, Rowan , Brown, David K , Glenister, Michael , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148282 , vital:38726 , doi: 10.1371/journal.pone.0166698
- Description: The development of automated servers to predict the three-dimensional structure of proteins has seen much progress over the years. These servers make calculations simpler, but largely exclude users from the process. In this study, we present the PRotein Interactive MOdeling (PRIMO) pipeline for homology modeling of protein monomers. The pipeline eases the multi-step modeling process, and reduces the workload required by the user, while still allowing engagement from the user during every step. Default parameters are given for each step, which can either be modified or supplemented with additional external input. PRIMO has been designed for users of varying levels of experience with homology modeling. The pipeline incorporates a user-friendly interface that makes it easy to alter parameters used during modeling.
- Full Text:
- Date Issued: 2017
Homology modeling and docking of AahII-Nanobody complexes reveal the epitope binding site on AahII scorpion toxin
- Ksouri, Ayoub, Ghedira, Kais, Abderrazek, Rahma Ben, Shankar, B A Gowri, Benkahla, Alia, Tastan Bishop, Özlem, Bouhaouala-Zahar, Balkis
- Authors: Ksouri, Ayoub , Ghedira, Kais , Abderrazek, Rahma Ben , Shankar, B A Gowri , Benkahla, Alia , Tastan Bishop, Özlem , Bouhaouala-Zahar, Balkis
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124604 , vital:35637 , https://doi.10.1016/j.bbrc.2018.01.036
- Description: Scorpion envenoming and its treatment is a public health problem in many parts of the world due to highly toxic venom polypeptides diffusing rapidly within the body of severely envenomed victims. Recently, 38 AahII-specific Nanobody sequences (Nbs) were retrieved from which the performance of NbAahII10 nanobody candidate, to neutralize the most poisonous venom compound namely AahII acting on sodium channels, was established. Herein, structural computational approach is conducted to elucidate the Nb-AahII interactions that support the biological characteristics, using Nb multiple sequence alignment (MSA) followed by modeling and molecular docking investigations (RosettaAntibody, ZDOCK software tools). Sequence and structural analysis showed two dissimilar residues of NbAahII10 CDR1 (Tyr27 and Tyr29) and an inserted polar residue Ser30 that appear to play an important role. Indeed, CDR3 region of NbAahII10 is characterized by a specific Met104 and two negatively chargedresidues Asp115 and Asp117. Complex dockings reveal that NbAahII17 and NbAahII38 share one common binding site on the surface of the AahII toxin divergent from the NbAahII10 one's. At least, a couple of NbAahII10 e AahII residue interactions (Gln38 e Asn44 and Arg62, His64, respectively) are mainly involved in the toxic AahII binding site. Altogether, this study gives valuable insights in the design and development of next generation of antivenom.
- Full Text:
- Date Issued: 2018
- Authors: Ksouri, Ayoub , Ghedira, Kais , Abderrazek, Rahma Ben , Shankar, B A Gowri , Benkahla, Alia , Tastan Bishop, Özlem , Bouhaouala-Zahar, Balkis
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124604 , vital:35637 , https://doi.10.1016/j.bbrc.2018.01.036
- Description: Scorpion envenoming and its treatment is a public health problem in many parts of the world due to highly toxic venom polypeptides diffusing rapidly within the body of severely envenomed victims. Recently, 38 AahII-specific Nanobody sequences (Nbs) were retrieved from which the performance of NbAahII10 nanobody candidate, to neutralize the most poisonous venom compound namely AahII acting on sodium channels, was established. Herein, structural computational approach is conducted to elucidate the Nb-AahII interactions that support the biological characteristics, using Nb multiple sequence alignment (MSA) followed by modeling and molecular docking investigations (RosettaAntibody, ZDOCK software tools). Sequence and structural analysis showed two dissimilar residues of NbAahII10 CDR1 (Tyr27 and Tyr29) and an inserted polar residue Ser30 that appear to play an important role. Indeed, CDR3 region of NbAahII10 is characterized by a specific Met104 and two negatively chargedresidues Asp115 and Asp117. Complex dockings reveal that NbAahII17 and NbAahII38 share one common binding site on the surface of the AahII toxin divergent from the NbAahII10 one's. At least, a couple of NbAahII10 e AahII residue interactions (Gln38 e Asn44 and Arg62, His64, respectively) are mainly involved in the toxic AahII binding site. Altogether, this study gives valuable insights in the design and development of next generation of antivenom.
- Full Text:
- Date Issued: 2018
Hepatitis C and HIV Coinfection in Developing Countries:
- Authors: Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/148228 , vital:38721 , ISBN 9780128032343 , https://books.google.co.za/books?id=XSmlCgAAQBAJanddq=hepatitis+c+in+developing+countriesandsource=gbs_navlinks_s
- Description: Because of the common routes of transmission, hepatitis C virus (HCV) coinfection with HIV is frequent. Of the 36.6 million HIV-infected individuals worldwide, about 25% are also coinfected with HCV. Developing countries face the greatest burden of coinfection. HIV infection has been shown to have a significant impact on the progression of chronic HCV, with a higher risk of cirrhosis and hepatocellular carcinoma (HCC). Because of the improvements in the management and treatment of HIV/AIDS in resource-limited countries, HCV/HIV coinfection is becoming a significant clinical problem and a major cause of morbidity and mortality. HCV/HIV coinfection is characterized by aggressive hepatic fibrogenesis, incidence of cirrhosis, and HCC. HCC is currently a major cause for liver-related deaths in HIV patients. Viral eradication has been difficult to attain with interferon and ribavirin therapies. Novel therapies with direct-acting antiviral agents have been promising for this population. However, access to such expensive regimen is far beyond the capabilities of most resource-limited countries. Yet, studies lag behind those for HCV monoinfection.
- Full Text:
- Date Issued: 2018
- Authors: Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/148228 , vital:38721 , ISBN 9780128032343 , https://books.google.co.za/books?id=XSmlCgAAQBAJanddq=hepatitis+c+in+developing+countriesandsource=gbs_navlinks_s
- Description: Because of the common routes of transmission, hepatitis C virus (HCV) coinfection with HIV is frequent. Of the 36.6 million HIV-infected individuals worldwide, about 25% are also coinfected with HCV. Developing countries face the greatest burden of coinfection. HIV infection has been shown to have a significant impact on the progression of chronic HCV, with a higher risk of cirrhosis and hepatocellular carcinoma (HCC). Because of the improvements in the management and treatment of HIV/AIDS in resource-limited countries, HCV/HIV coinfection is becoming a significant clinical problem and a major cause of morbidity and mortality. HCV/HIV coinfection is characterized by aggressive hepatic fibrogenesis, incidence of cirrhosis, and HCC. HCC is currently a major cause for liver-related deaths in HIV patients. Viral eradication has been difficult to attain with interferon and ribavirin therapies. Novel therapies with direct-acting antiviral agents have been promising for this population. However, access to such expensive regimen is far beyond the capabilities of most resource-limited countries. Yet, studies lag behind those for HCV monoinfection.
- Full Text:
- Date Issued: 2018
SANCDB: a South African natural compound database
- Hatherley, Rowan, Brown, David K, Musyoka, Thommas M, Penkler, David L, Faya, Ngonidzashe, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Hatherley, Rowan , Brown, David K , Musyoka, Thommas M , Penkler, David L , Faya, Ngonidzashe , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162890 , vital:40994 , DOI 10.1186/s13321-015-0080-89
- Description: Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
- Full Text:
- Date Issued: 2015
- Authors: Hatherley, Rowan , Brown, David K , Musyoka, Thommas M , Penkler, David L , Faya, Ngonidzashe , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162890 , vital:40994 , DOI 10.1186/s13321-015-0080-89
- Description: Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
- Full Text:
- Date Issued: 2015
The role of structural bioinformatics in drug discovery via computational SNP analysis–a proposed protocol for analyzing variation at the protein level:
- Brown, David K, Tastan Bishop, Özlem
- Authors: Brown, David K , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162914 , vital:40996 , doi: 10.1016/j.gheart.2017.01.009
- Description: With the completion of the human genome project at the beginning of the 21st century, the biological sciences entered an unprecedented age of data generation, and made its first steps towards an era of personalized medicine. This abundance of sequence data has led to the proliferation of numerous sequence-based techniques for associating variation with disease, such as Genome-Wide Association Studies (GWAS) and Candidate Gene Association Studies (CGAS). However, these statistical methods do not provide an understanding of the functional effects of variation. Structure-based drug discovery and design is increasingly incorporating structural bioinformatics techniques to model and analyze protein targets, perform large scale virtual screening to identify hit to lead compounds, and simulate molecular interactions. These techniques are fast, cost-effective, and complement existing experimental techniques such as High Throughput Sequencing (HTS).
- Full Text:
- Date Issued: 2017
- Authors: Brown, David K , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162914 , vital:40996 , doi: 10.1016/j.gheart.2017.01.009
- Description: With the completion of the human genome project at the beginning of the 21st century, the biological sciences entered an unprecedented age of data generation, and made its first steps towards an era of personalized medicine. This abundance of sequence data has led to the proliferation of numerous sequence-based techniques for associating variation with disease, such as Genome-Wide Association Studies (GWAS) and Candidate Gene Association Studies (CGAS). However, these statistical methods do not provide an understanding of the functional effects of variation. Structure-based drug discovery and design is increasingly incorporating structural bioinformatics techniques to model and analyze protein targets, perform large scale virtual screening to identify hit to lead compounds, and simulate molecular interactions. These techniques are fast, cost-effective, and complement existing experimental techniques such as High Throughput Sequencing (HTS).
- Full Text:
- Date Issued: 2017
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:
- Date Issued: 2020
- 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:
- Date Issued: 2020
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:
- Date Issued: 2020
- 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:
- Date Issued: 2020