The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets
Diphtheria is an acute and highly infectious disease, previously regarded as endemic in nature but vaccine-preventable, is caused by Corynebacterium diphtheriae (Cd). In this work, we used an in silico approach along the 13 complete genome sequences of C. diphtheriae followed by a computational asse...
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2018
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_16648021_v9_nFEB_p_Hassan http://hdl.handle.net/20.500.12110/paper_16648021_v9_nFEB_p_Hassan |
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paper:paper_16648021_v9_nFEB_p_Hassan2023-06-08T16:26:09Z The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets Corynebacterium diphtheria Druggable genome Global druggable (GD) Highly druggable (HD) Pocketome Putative therapeutic targets Structural proteomics adenosine triphosphate phosphoribosyltransferase apyrase fructose 1,6 bisphosphate fructose bisphosphatase new drug proteome ribosome protein amino acid sequence Article binding site cellular distribution computer model conserved sequence Corynebacterium diphtheriae drug database drug targeting druggable pocketome enzyme active site gene fusion gene sequence infectious agent nonhuman open reading frame Protein Data Bank protein protein interaction sequence homology structural model structural proteomics structure analysis three dimensional imaging Diphtheria is an acute and highly infectious disease, previously regarded as endemic in nature but vaccine-preventable, is caused by Corynebacterium diphtheriae (Cd). In this work, we used an in silico approach along the 13 complete genome sequences of C. diphtheriae followed by a computational assessment of structural information of the binding sites to characterize the "pocketome druggability." To this end, we first computed the "modelome" (3D structures of a complete genome) of a randomly selected reference strain Cd NCTC13129; that had 13,763 open reading frames (ORFs) and resulted in 1,253 (~9%) structure models. The amino acid sequences of these modeled structures were compared with the remaining 12 genomes and consequently, 438 conserved protein sequences were obtained. The RCSB-PDB database was consulted to check the template structures for these conserved proteins and as a result, 401 adequate 3D models were obtained. We subsequently predicted the protein pockets for the obtained set of models and kept only the conserved pockets that had highly druggable (HD) values (137 across all strains). Later, an off-target host homology analyses was performed considering the human proteome using NCBI database. Furthermore, the gene essentiality analysis was carried out that gave a final set of 10-conserved targets possessing highly druggable protein pockets. To check the target identification robustness of the pipeline used in this work, we crosschecked the final target list with another in-house target identification approach for C. diphtheriae thereby obtaining three common targets, these were; hisE-phosphoribosyl-ATP pyrophosphatase, glpX-fructose 1,6-bisphosphatase II, and rpsH-30S ribosomal protein S8. Our predicted results suggest that the in silico approach used could potentially aid in experimental polypharmacological target determination in C. diphtheriae and other pathogens, thereby, might complement the existing and new drug-discovery pipelines. © 2018 Hassan, Jamal, Radusky, Tiwari, Ullah, Ali, Behramand, de Carvalho, Shams, Khan, Figueiredo, Barh, Ghosh, Silva, Baumbach, Röttger, Turjanski and Azevedo. 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_16648021_v9_nFEB_p_Hassan http://hdl.handle.net/20.500.12110/paper_16648021_v9_nFEB_p_Hassan |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Corynebacterium diphtheria Druggable genome Global druggable (GD) Highly druggable (HD) Pocketome Putative therapeutic targets Structural proteomics adenosine triphosphate phosphoribosyltransferase apyrase fructose 1,6 bisphosphate fructose bisphosphatase new drug proteome ribosome protein amino acid sequence Article binding site cellular distribution computer model conserved sequence Corynebacterium diphtheriae drug database drug targeting druggable pocketome enzyme active site gene fusion gene sequence infectious agent nonhuman open reading frame Protein Data Bank protein protein interaction sequence homology structural model structural proteomics structure analysis three dimensional imaging |
| spellingShingle |
Corynebacterium diphtheria Druggable genome Global druggable (GD) Highly druggable (HD) Pocketome Putative therapeutic targets Structural proteomics adenosine triphosphate phosphoribosyltransferase apyrase fructose 1,6 bisphosphate fructose bisphosphatase new drug proteome ribosome protein amino acid sequence Article binding site cellular distribution computer model conserved sequence Corynebacterium diphtheriae drug database drug targeting druggable pocketome enzyme active site gene fusion gene sequence infectious agent nonhuman open reading frame Protein Data Bank protein protein interaction sequence homology structural model structural proteomics structure analysis three dimensional imaging The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets |
| topic_facet |
Corynebacterium diphtheria Druggable genome Global druggable (GD) Highly druggable (HD) Pocketome Putative therapeutic targets Structural proteomics adenosine triphosphate phosphoribosyltransferase apyrase fructose 1,6 bisphosphate fructose bisphosphatase new drug proteome ribosome protein amino acid sequence Article binding site cellular distribution computer model conserved sequence Corynebacterium diphtheriae drug database drug targeting druggable pocketome enzyme active site gene fusion gene sequence infectious agent nonhuman open reading frame Protein Data Bank protein protein interaction sequence homology structural model structural proteomics structure analysis three dimensional imaging |
| description |
Diphtheria is an acute and highly infectious disease, previously regarded as endemic in nature but vaccine-preventable, is caused by Corynebacterium diphtheriae (Cd). In this work, we used an in silico approach along the 13 complete genome sequences of C. diphtheriae followed by a computational assessment of structural information of the binding sites to characterize the "pocketome druggability." To this end, we first computed the "modelome" (3D structures of a complete genome) of a randomly selected reference strain Cd NCTC13129; that had 13,763 open reading frames (ORFs) and resulted in 1,253 (~9%) structure models. The amino acid sequences of these modeled structures were compared with the remaining 12 genomes and consequently, 438 conserved protein sequences were obtained. The RCSB-PDB database was consulted to check the template structures for these conserved proteins and as a result, 401 adequate 3D models were obtained. We subsequently predicted the protein pockets for the obtained set of models and kept only the conserved pockets that had highly druggable (HD) values (137 across all strains). Later, an off-target host homology analyses was performed considering the human proteome using NCBI database. Furthermore, the gene essentiality analysis was carried out that gave a final set of 10-conserved targets possessing highly druggable protein pockets. To check the target identification robustness of the pipeline used in this work, we crosschecked the final target list with another in-house target identification approach for C. diphtheriae thereby obtaining three common targets, these were; hisE-phosphoribosyl-ATP pyrophosphatase, glpX-fructose 1,6-bisphosphatase II, and rpsH-30S ribosomal protein S8. Our predicted results suggest that the in silico approach used could potentially aid in experimental polypharmacological target determination in C. diphtheriae and other pathogens, thereby, might complement the existing and new drug-discovery pipelines. © 2018 Hassan, Jamal, Radusky, Tiwari, Ullah, Ali, Behramand, de Carvalho, Shams, Khan, Figueiredo, Barh, Ghosh, Silva, Baumbach, Röttger, Turjanski and Azevedo. |
| title |
The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets |
| title_short |
The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets |
| title_full |
The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets |
| title_fullStr |
The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets |
| title_full_unstemmed |
The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets |
| title_sort |
druggable pocketome of corynebacterium diphtheriae: a new approach for in silico putative druggable targets |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_16648021_v9_nFEB_p_Hassan http://hdl.handle.net/20.500.12110/paper_16648021_v9_nFEB_p_Hassan |
| _version_ |
1768542757861720064 |