An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets
Background: The bacterium Corynebacterium pseudotuberculosis (Cp) causes caseous lymphadenitis (CLA), mastitis, ulcerative lymphangitis, and oedema in a number of hosts, comprising ruminants, thereby intimidating economic and dairy industries worldwide. So far there is no effective drug or vaccine a...
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todo:paper_14712164_v16_n5_p_Radusky2023-10-03T16:17:46Z An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets Radusky, L.G. Hassan, S.S. Lanzarotti, E. Tiwari, S. Jamal, S.B. Ali, J. Ali, A. Ferreira, R.S. Barh, D. Silva, A. Turjanski, A.G. Azevedo, V.A.C. 3 isopropylmalate dehydratase small subunit 50S ribosomal protein L30 bacterial protein hydrolyase proteome replication initiator protein DnaA ribosome protein unclassified drug antiinfective agent Article bacterial genome bacterial strain biotype computer model Corynebacterium pseudotuberculosis drug targeting genome analysis host nonhuman open reading frame pathogenicity island protein analysis protein structure structural homology structural proteomics structure analysis algorithm animal bacterial genome binding site biology Corynebacterium Infections Corynebacterium pseudotuberculosis drug effects genetics human nucleotide sequence procedures proteomics veterinary Algorithms Animals Anti-Bacterial Agents Base Sequence Binding Sites Computational Biology Corynebacterium Infections Corynebacterium pseudotuberculosis Genome, Bacterial Humans Open Reading Frames Proteomics Background: The bacterium Corynebacterium pseudotuberculosis (Cp) causes caseous lymphadenitis (CLA), mastitis, ulcerative lymphangitis, and oedema in a number of hosts, comprising ruminants, thereby intimidating economic and dairy industries worldwide. So far there is no effective drug or vaccine available against Cp. Previously, a pan-genomic analysis was performed for both biovar equi and biovar ovis and a Pathogenicity Islands (PAIS) analysis within the strains highlighted a large set of proteins that could be relevant therapeutic targets for controlling the onset of CLA. In the present work, a structural druggability analysis pipeline was accomplished along 15 previously sequenced Cp strains from both biovar equi and biovar ovis. Methods and results: We computed the whole modelome of a reference strain Cp1002 (NCBI Accession: NC_017300.1) and then the homology models of proteins, of 14 different Cp strains, with high identity (≥ 85%) to the reference strain were also done. Druggability score of all proteins pockets was calculated and only those targets that have a highly druggable (HD) pocket in all strains were kept, a set of 58 proteins. Finally, this information was merged with the previous PAIS analysis giving two possible highly relevant targets to conduct drug discovery projects. Also, off-targeting information against host organisms, including Homo sapiens and a further analysis for protein essentiality provided a final set of 31 druggable, essential and non-host homologous targets, tabulated in table S4, additional file 1. Out of 31 globally druggable targets, 9 targets have already been reported in other pathogenic microorganisms, 3 of them (3-isopropylmalate dehydratase small subunit, 50S ribosomal protein L30, Chromosomal replication initiator protein DnaA) in C. pseudotuberculosis. Conclusion: Overall we provide valuable information of possible targets against C. pseudotuberculosis where some of these targets have already been reported in other microorganisms for drug discovery projects, also discarding targets that might be physiologically relevant but are not amenable for drug binding. We propose that the constructed in silico dataset might serve as a guidance for the scientific community to have a better understanding while selecting putative therapeutic protein candidates as druggable ones as effective measures against C. pseudotuberculosis. © 2015 Radusky et al. Fil:Turjanski, A.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_14712164_v16_n5_p_Radusky |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
3 isopropylmalate dehydratase small subunit 50S ribosomal protein L30 bacterial protein hydrolyase proteome replication initiator protein DnaA ribosome protein unclassified drug antiinfective agent Article bacterial genome bacterial strain biotype computer model Corynebacterium pseudotuberculosis drug targeting genome analysis host nonhuman open reading frame pathogenicity island protein analysis protein structure structural homology structural proteomics structure analysis algorithm animal bacterial genome binding site biology Corynebacterium Infections Corynebacterium pseudotuberculosis drug effects genetics human nucleotide sequence procedures proteomics veterinary Algorithms Animals Anti-Bacterial Agents Base Sequence Binding Sites Computational Biology Corynebacterium Infections Corynebacterium pseudotuberculosis Genome, Bacterial Humans Open Reading Frames Proteomics |
| spellingShingle |
3 isopropylmalate dehydratase small subunit 50S ribosomal protein L30 bacterial protein hydrolyase proteome replication initiator protein DnaA ribosome protein unclassified drug antiinfective agent Article bacterial genome bacterial strain biotype computer model Corynebacterium pseudotuberculosis drug targeting genome analysis host nonhuman open reading frame pathogenicity island protein analysis protein structure structural homology structural proteomics structure analysis algorithm animal bacterial genome binding site biology Corynebacterium Infections Corynebacterium pseudotuberculosis drug effects genetics human nucleotide sequence procedures proteomics veterinary Algorithms Animals Anti-Bacterial Agents Base Sequence Binding Sites Computational Biology Corynebacterium Infections Corynebacterium pseudotuberculosis Genome, Bacterial Humans Open Reading Frames Proteomics Radusky, L.G. Hassan, S.S. Lanzarotti, E. Tiwari, S. Jamal, S.B. Ali, J. Ali, A. Ferreira, R.S. Barh, D. Silva, A. Turjanski, A.G. Azevedo, V.A.C. An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets |
| topic_facet |
3 isopropylmalate dehydratase small subunit 50S ribosomal protein L30 bacterial protein hydrolyase proteome replication initiator protein DnaA ribosome protein unclassified drug antiinfective agent Article bacterial genome bacterial strain biotype computer model Corynebacterium pseudotuberculosis drug targeting genome analysis host nonhuman open reading frame pathogenicity island protein analysis protein structure structural homology structural proteomics structure analysis algorithm animal bacterial genome binding site biology Corynebacterium Infections Corynebacterium pseudotuberculosis drug effects genetics human nucleotide sequence procedures proteomics veterinary Algorithms Animals Anti-Bacterial Agents Base Sequence Binding Sites Computational Biology Corynebacterium Infections Corynebacterium pseudotuberculosis Genome, Bacterial Humans Open Reading Frames Proteomics |
| description |
Background: The bacterium Corynebacterium pseudotuberculosis (Cp) causes caseous lymphadenitis (CLA), mastitis, ulcerative lymphangitis, and oedema in a number of hosts, comprising ruminants, thereby intimidating economic and dairy industries worldwide. So far there is no effective drug or vaccine available against Cp. Previously, a pan-genomic analysis was performed for both biovar equi and biovar ovis and a Pathogenicity Islands (PAIS) analysis within the strains highlighted a large set of proteins that could be relevant therapeutic targets for controlling the onset of CLA. In the present work, a structural druggability analysis pipeline was accomplished along 15 previously sequenced Cp strains from both biovar equi and biovar ovis. Methods and results: We computed the whole modelome of a reference strain Cp1002 (NCBI Accession: NC_017300.1) and then the homology models of proteins, of 14 different Cp strains, with high identity (≥ 85%) to the reference strain were also done. Druggability score of all proteins pockets was calculated and only those targets that have a highly druggable (HD) pocket in all strains were kept, a set of 58 proteins. Finally, this information was merged with the previous PAIS analysis giving two possible highly relevant targets to conduct drug discovery projects. Also, off-targeting information against host organisms, including Homo sapiens and a further analysis for protein essentiality provided a final set of 31 druggable, essential and non-host homologous targets, tabulated in table S4, additional file 1. Out of 31 globally druggable targets, 9 targets have already been reported in other pathogenic microorganisms, 3 of them (3-isopropylmalate dehydratase small subunit, 50S ribosomal protein L30, Chromosomal replication initiator protein DnaA) in C. pseudotuberculosis. Conclusion: Overall we provide valuable information of possible targets against C. pseudotuberculosis where some of these targets have already been reported in other microorganisms for drug discovery projects, also discarding targets that might be physiologically relevant but are not amenable for drug binding. We propose that the constructed in silico dataset might serve as a guidance for the scientific community to have a better understanding while selecting putative therapeutic protein candidates as druggable ones as effective measures against C. pseudotuberculosis. © 2015 Radusky et al. |
| format |
JOUR |
| author |
Radusky, L.G. Hassan, S.S. Lanzarotti, E. Tiwari, S. Jamal, S.B. Ali, J. Ali, A. Ferreira, R.S. Barh, D. Silva, A. Turjanski, A.G. Azevedo, V.A.C. |
| author_facet |
Radusky, L.G. Hassan, S.S. Lanzarotti, E. Tiwari, S. Jamal, S.B. Ali, J. Ali, A. Ferreira, R.S. Barh, D. Silva, A. Turjanski, A.G. Azevedo, V.A.C. |
| author_sort |
Radusky, L.G. |
| title |
An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets |
| title_short |
An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets |
| title_full |
An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets |
| title_fullStr |
An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets |
| title_full_unstemmed |
An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets |
| title_sort |
integrated structural proteomics approach along the druggable genome of corynebacterium pseudotuberculosis species for putative druggable targets |
| url |
http://hdl.handle.net/20.500.12110/paper_14712164_v16_n5_p_Radusky |
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