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
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
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
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:
- Date Issued: 2020
- 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:
- Date Issued: 2020
Improving fold resistance prediction of HIV-1 against protease and reverse transcriptase inhibitors using artificial neural networks:
- Amamuddy, Olivier S, Bishop, Nigel T, Tastan Bishop, Özlem
- Authors: Amamuddy, Olivier S , Bishop, Nigel T , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148261 , vital:38724 , https://0-doi.org.wam.seals.ac.za/10.1186/s12859-017-1782-x
- Description: Drug resistance in HIV treatment is still a worldwide problem. Predicting resistance to antiretrovirals (ARVs) before starting any treatment is important. Prediction accuracy is essential, as low-accuracy predictions increase the risk of prescribing sub-optimal drug regimens leading to patients developing resistance sooner. Artificial Neural Networks (ANNs) are a powerful tool that would be able to assist in drug resistance prediction. In this study, we constrained the dataset to subtype B, sacrificing generalizability for a higher predictive performance, and demonstrated that the predictive quality of the ANN regression models have definite improvement for most ARVs.
- Full Text:
- Date Issued: 2017
- Authors: Amamuddy, Olivier S , Bishop, Nigel T , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148261 , vital:38724 , https://0-doi.org.wam.seals.ac.za/10.1186/s12859-017-1782-x
- Description: Drug resistance in HIV treatment is still a worldwide problem. Predicting resistance to antiretrovirals (ARVs) before starting any treatment is important. Prediction accuracy is essential, as low-accuracy predictions increase the risk of prescribing sub-optimal drug regimens leading to patients developing resistance sooner. Artificial Neural Networks (ANNs) are a powerful tool that would be able to assist in drug resistance prediction. In this study, we constrained the dataset to subtype B, sacrificing generalizability for a higher predictive performance, and demonstrated that the predictive quality of the ANN regression models have definite improvement for most ARVs.
- Full Text:
- Date Issued: 2017
Characterizing early drug resistance-related events using geometric ensembles from HIV protease dynamics:
- Amamuddy, Olivier S, Bishop, Nigel T, Tastan Bishop, Özlem
- Authors: Amamuddy, Olivier S , Bishop, Nigel T , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148126 , vital:38712 , DOI: 10.1038/s41598-018-36041-8
- Description: The use of antiretrovirals (ARVs) has drastically improved the life quality and expectancy of HIV patients since their introduction in health care. Several millions are still afflicted worldwide by HIV and ARV resistance is a constant concern for both healthcare practitioners and patients, as while treatment options are finite, the virus constantly adapts via complex mutation patterns to select for resistant strains under the pressure of drug treatment. The HIV protease is a crucial enzyme for viral maturation and has been a game changing drug target since the first application. Due to similarities in protease inhibitor designs, drug cross-resistance is not uncommon across ARVs of the same class.
- Full Text:
- Date Issued: 2018
- Authors: Amamuddy, Olivier S , Bishop, Nigel T , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148126 , vital:38712 , DOI: 10.1038/s41598-018-36041-8
- Description: The use of antiretrovirals (ARVs) has drastically improved the life quality and expectancy of HIV patients since their introduction in health care. Several millions are still afflicted worldwide by HIV and ARV resistance is a constant concern for both healthcare practitioners and patients, as while treatment options are finite, the virus constantly adapts via complex mutation patterns to select for resistant strains under the pressure of drug treatment. The HIV protease is a crucial enzyme for viral maturation and has been a game changing drug target since the first application. Due to similarities in protease inhibitor designs, drug cross-resistance is not uncommon across ARVs of the same class.
- Full Text:
- Date Issued: 2018
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
Establishing computational approaches towards identifying malarial allosteric modulators: a case study of plasmodium falciparum hsp70s
- Amusengeri, Arnold, Astl, Lindy, Lobb, Kevin A, Verkhivker, Gennady M, Tastan Bishop, Özlem
- Authors: Amusengeri, Arnold , Astl, Lindy , Lobb, Kevin A , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163000 , vital:41003 , https://doi.org/10.3390/ijms20225574
- Description: Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control mechanisms. Yet, studies on designing allosteric modulators against them are limited. Here, we identified allosteric modulators (SANC190 and SANC651) against P. falciparum Hsp70-1 and Hsp70-x, affecting the conformational dynamics of the proteins, delicately balanced by the endogenous ligands. Previously, we established a pipeline to identify allosteric sites and modulators. This study also further investigated alternative approaches to speed up the process by comparing all atom molecular dynamics simulations and dynamic residue network analysis with the coarse-grained (CG) versions of the calculations. Betweenness centrality (BC) profiles for PfHsp70-1 and PfHsp70-x derived from CG simulations not only revealed similar trends but also pointed to the same functional regions and specific residues corresponding to BC profile peaks.
- Full Text:
- Date Issued: 2019
- Authors: Amusengeri, Arnold , Astl, Lindy , Lobb, Kevin A , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163000 , vital:41003 , https://doi.org/10.3390/ijms20225574
- Description: Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control mechanisms. Yet, studies on designing allosteric modulators against them are limited. Here, we identified allosteric modulators (SANC190 and SANC651) against P. falciparum Hsp70-1 and Hsp70-x, affecting the conformational dynamics of the proteins, delicately balanced by the endogenous ligands. Previously, we established a pipeline to identify allosteric sites and modulators. This study also further investigated alternative approaches to speed up the process by comparing all atom molecular dynamics simulations and dynamic residue network analysis with the coarse-grained (CG) versions of the calculations. Betweenness centrality (BC) profiles for PfHsp70-1 and PfHsp70-x derived from CG simulations not only revealed similar trends but also pointed to the same functional regions and specific residues corresponding to BC profile peaks.
- Full Text:
- Date Issued: 2019
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:
- Date Issued: 2020
- 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:
- Date Issued: 2020
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
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
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
Role of structural bioinformatics in drug discovery by computational SNP analysis: 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/10962/125921 , vital:35832 , https://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 toward 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 and candidate gene association studies. 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. In this paper, we discuss the contributions of structural bioinformatics to drug discovery, focusing particularly on the analysis of nonsynonymous single nucleotide polymorphisms. We conclude by suggesting a protocol for future analyses of the structural effects of nonsynonymous single nucleotide polymorphisms on proteins and protein complexes.
- Full Text:
- Date Issued: 2017
- Authors: Brown, David K , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125921 , vital:35832 , https://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 toward 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 and candidate gene association studies. 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. In this paper, we discuss the contributions of structural bioinformatics to drug discovery, focusing particularly on the analysis of nonsynonymous single nucleotide polymorphisms. We conclude by suggesting a protocol for future analyses of the structural effects of nonsynonymous single nucleotide polymorphisms on proteins and protein complexes.
- Full Text:
- Date Issued: 2017
JMS: an open source workflow management system and web-based cluster front-end for high performance computing
- Brown, David K, Penkler, David L, Musyoka, Thommas M, Tastan Bishop, Özlem
- Authors: Brown, David K , Penkler, David L , Musyoka, Thommas M , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162880 , vital:40993 , doi:10.1371/journal.pone.0134273
- 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 high performance computing (HPC) 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. We have developed the Job Management System (JMS), a workflow management system and web interface for high performance computing (HPC). JMS provides users with a user-friendly web interface for creating complex workflows with multiple stages. It integrates this workflow functionality with the resource manager, a tool that is used to control and manage batch jobs on HPC clusters. As such, JMS combines workflow management functionality with cluster administration functionality.
- Full Text:
- Date Issued: 2015
- Authors: Brown, David K , Penkler, David L , Musyoka, Thommas M , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162880 , vital:40993 , doi:10.1371/journal.pone.0134273
- 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 high performance computing (HPC) 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. We have developed the Job Management System (JMS), a workflow management system and web interface for high performance computing (HPC). JMS provides users with a user-friendly web interface for creating complex workflows with multiple stages. It integrates this workflow functionality with the resource manager, a tool that is used to control and manage batch jobs on HPC clusters. As such, JMS combines workflow management functionality with cluster administration functionality.
- Full Text:
- Date Issued: 2015
HUMA: A platform for the analysis of genetic variation in humans
- Brown, David K, Tastan Bishop, Özlem
- Authors: Brown, David K , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124653 , vital:35642 , https://doi.10.1002/humu.23334
- Description: The completion of the human genome project at the beginning of the 21st century, along with the rapid advancement of sequencing technologies thereafter, has resulted in exponential growth of biological data. In genetics, this has given rise to numerous variation databases, created to store and annotate the ever-expanding dataset of known mutations. Usually, these databases focus on variation at the sequence level. Few databases focus on the analysis of variation at the 3D level, that is, mapping, visualizing, and determining the effects of variation in protein structures. Additionally, these Web servers seldom incorporate tools to help analyze these data. Here, we present the Human Mutation Analysis (HUMA) Web server and database. HUMA integrates sequence, structure, variation, and disease data into a single, connected database. A user-friendly interface provides click-based data access and visualization, whereas a RESTfulWebAPI provides programmatic access to the data. Tools have been integrated into HUMA to allow initial analyses to be carried out on the server. Furthermore, users can upload their private variation datasets, which are automatically mapped to public data and can be analyzed using the integrated tools. HUMA is freely accessible at https://huma.rubi.ru.ac.za.
- Full Text:
- Date Issued: 2018
- Authors: Brown, David K , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124653 , vital:35642 , https://doi.10.1002/humu.23334
- Description: The completion of the human genome project at the beginning of the 21st century, along with the rapid advancement of sequencing technologies thereafter, has resulted in exponential growth of biological data. In genetics, this has given rise to numerous variation databases, created to store and annotate the ever-expanding dataset of known mutations. Usually, these databases focus on variation at the sequence level. Few databases focus on the analysis of variation at the 3D level, that is, mapping, visualizing, and determining the effects of variation in protein structures. Additionally, these Web servers seldom incorporate tools to help analyze these data. Here, we present the Human Mutation Analysis (HUMA) Web server and database. HUMA integrates sequence, structure, variation, and disease data into a single, connected database. A user-friendly interface provides click-based data access and visualization, whereas a RESTfulWebAPI provides programmatic access to the data. Tools have been integrated into HUMA to allow initial analyses to be carried out on the server. Furthermore, users can upload their private variation datasets, which are automatically mapped to public data and can be analyzed using the integrated tools. HUMA is freely accessible at https://huma.rubi.ru.ac.za.
- Full Text:
- Date Issued: 2018
MD-TASK: a software suite for analyzing molecular dynamics trajectories
- Brown, David K, Penkler, David L, Amamuddy, Olivier S, Ross, Caroline J, Atilgan, Ali R, Atilgan, Canan, Tastan Bishop, Özlem
- Authors: Brown, David K , Penkler, David L , Amamuddy, Olivier S , Ross, Caroline J , Atilgan, Ali R , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125138 , vital:35735 , https://doi.10.1093/bioinformatics/btx349
- Description: Molecular dynamics (MD) determines the physical motions of atoms of a biological macromolecule in a cell-like environment and is an important method in structural bioinformatics. Traditionally, measurements such as root mean square deviation, root mean square fluctuation, radius of gyration, and various energy measures have been used to analyze MD simulations. Here, we present MD-TASK, a novel software suite that employs graph theory techniques, perturbation response scanning, and dynamic cross-correlation to provide unique ways for analyzing MD trajectories.
- Full Text:
- Date Issued: 2017
- Authors: Brown, David K , Penkler, David L , Amamuddy, Olivier S , Ross, Caroline J , Atilgan, Ali R , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125138 , vital:35735 , https://doi.10.1093/bioinformatics/btx349
- Description: Molecular dynamics (MD) determines the physical motions of atoms of a biological macromolecule in a cell-like environment and is an important method in structural bioinformatics. Traditionally, measurements such as root mean square deviation, root mean square fluctuation, radius of gyration, and various energy measures have been used to analyze MD simulations. Here, we present MD-TASK, a novel software suite that employs graph theory techniques, perturbation response scanning, and dynamic cross-correlation to provide unique ways for analyzing MD trajectories.
- Full Text:
- Date Issued: 2017
The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype:
- Cornick, Jennifer E, Tastan Bishop, Özlem, Yalcin, Feyruz, Kiran, Anmol M, Kumwenda, Benjamin, Chaguza, Chrispin, Govindpershad, Shanil, Ousmane, Sani, Senghore, Madikay, du Plessis, Mignon, Pluschke, Gerd, 1952-, Ebruke, Chinelo, McGee, Lesley, Sigaùque , Beutel, Collard, Jean-Marc, Bentley, Stephen D, Kadioglu , Aras, Antonio, Martin, von Gottberg, Anne, French, Neil, Klugman, Keith P, Heyderman, Robert S, Alderson, Mark, Everett, Dean B
- Authors: Cornick, Jennifer E , Tastan Bishop, Özlem , Yalcin, Feyruz , Kiran, Anmol M , Kumwenda, Benjamin , Chaguza, Chrispin , Govindpershad, Shanil , Ousmane, Sani , Senghore, Madikay , du Plessis, Mignon , Pluschke, Gerd, 1952- , Ebruke, Chinelo , McGee, Lesley , Sigaùque , Beutel , Collard, Jean-Marc , Bentley, Stephen D , Kadioglu , Aras , Antonio, Martin , von Gottberg, Anne , French, Neil , Klugman, Keith P , Heyderman, Robert S , Alderson, Mark , Everett, Dean B
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148318 , vital:38729 , DOI: 10.1016/j.vaccine.2016.12.037
- Description: Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1.
- Full Text:
- Date Issued: 2017
- Authors: Cornick, Jennifer E , Tastan Bishop, Özlem , Yalcin, Feyruz , Kiran, Anmol M , Kumwenda, Benjamin , Chaguza, Chrispin , Govindpershad, Shanil , Ousmane, Sani , Senghore, Madikay , du Plessis, Mignon , Pluschke, Gerd, 1952- , Ebruke, Chinelo , McGee, Lesley , Sigaùque , Beutel , Collard, Jean-Marc , Bentley, Stephen D , Kadioglu , Aras , Antonio, Martin , von Gottberg, Anne , French, Neil , Klugman, Keith P , Heyderman, Robert S , Alderson, Mark , Everett, Dean B
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148318 , vital:38729 , DOI: 10.1016/j.vaccine.2016.12.037
- Description: Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1.
- Full Text:
- Date Issued: 2017
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
In silico study of Plasmodium 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) for identification of novel inhibitors from SANCDB:
- 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/10962/162687 , vital:40973 , https://doi.org/10.21955/aasopenres.1114960.1
- Description: In this study, we intended to find potential 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) inhibitors as antimalarial drugs from the South African National Compound Database (SANCDB; https://sancdb.rubi.ru.ac.za) using computational tools.
- 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/10962/162687 , vital:40973 , https://doi.org/10.21955/aasopenres.1114960.1
- Description: In this study, we intended to find potential 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) inhibitors as antimalarial drugs from the South African National Compound Database (SANCDB; https://sancdb.rubi.ru.ac.za) using computational tools.
- Full Text:
- Date Issued: 2019
Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
- Diallo, Bakary N, Swart, Tarryn, Hoppe, Heinrich C, Tastan Bishop, Özlem, Lobb, Kevin A
- Authors: Diallo, Bakary N , Swart, Tarryn , Hoppe, Heinrich C , Tastan Bishop, Özlem , Lobb, Kevin A
- Date: 2021
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/177531 , vital:42830 , https://doi.org/10.1038/s41598-020-80722-2
- Description: Malaria elimination can benefit from time and cost-efficient approaches for antimalarials such as drug repurposing. In this work, 796 DrugBank compounds were screened against 36 Plasmodium falciparum targets using QuickVina-W. Hits were selected after rescoring using GRaph Interaction Matching (GRIM) and ligand efficiency metrics: surface efficiency index (SEI), binding efficiency index (BEI) and lipophilic efficiency (LipE). They were further evaluated in Molecular dynamics (MD). Twenty-five protein–ligand complexes were finally retained from the 28,656 (36×796) dockings.
- Full Text:
- Date Issued: 2021
- Authors: Diallo, Bakary N , Swart, Tarryn , Hoppe, Heinrich C , Tastan Bishop, Özlem , Lobb, Kevin A
- Date: 2021
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/177531 , vital:42830 , https://doi.org/10.1038/s41598-020-80722-2
- Description: Malaria elimination can benefit from time and cost-efficient approaches for antimalarials such as drug repurposing. In this work, 796 DrugBank compounds were screened against 36 Plasmodium falciparum targets using QuickVina-W. Hits were selected after rescoring using GRaph Interaction Matching (GRIM) and ligand efficiency metrics: surface efficiency index (SEI), binding efficiency index (BEI) and lipophilic efficiency (LipE). They were further evaluated in Molecular dynamics (MD). Twenty-five protein–ligand complexes were finally retained from the 28,656 (36×796) dockings.
- Full Text:
- Date Issued: 2021