The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets

Syed S. Hassan, Syed B. Jamal, Leandro G. Radusky, Sandeep Tiwari, Asad Ullah, Javed Ali, Behramand, Paulo V.S.D. de Carvalho, Rida Shams, Sabir Khan, Henrique C.P. Figueiredo, Debmalya Barh, Preetam Ghosh, Artur Silva, Jan Baumbach, Richard Röttger, Adrián G. Turjanski, Vasco A.C. Azevedo

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Abstract

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.

Original languageEnglish
Article number44
JournalFrontiers in Genetics
Volume9
Number of pages9
ISSN1664-8021
DOIs
Publication statusPublished - 2018

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Corynebacterium diphtheriae
Computer Simulation
Proteins
Databases
Fructose-Bisphosphatase
Diphtheria
Proteome
Open Reading Frames

Keywords

  • Corynebacterium diphtheria
  • Druggable genome
  • Global druggable (GD)
  • Highly druggable (HD)
  • Pocketome
  • Putative therapeutic targets
  • Structural proteomics

Cite this

Hassan, S. S., Jamal, S. B., Radusky, L. G., Tiwari, S., Ullah, A., Ali, J., ... Azevedo, V. A. C. (2018). The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets. Frontiers in Genetics, 9, [44]. https://doi.org/10.3389/fgene.2018.00044
Hassan, Syed S. ; Jamal, Syed B. ; Radusky, Leandro G. ; Tiwari, Sandeep ; Ullah, Asad ; Ali, Javed ; Behramand ; de Carvalho, Paulo V.S.D. ; Shams, Rida ; Khan, Sabir ; Figueiredo, Henrique C.P. ; Barh, Debmalya ; Ghosh, Preetam ; Silva, Artur ; Baumbach, Jan ; Röttger, Richard ; Turjanski, Adrián G. ; Azevedo, Vasco A.C. / The druggable pocketome of Corynebacterium diphtheriae : A new approach for in silico putative druggable targets. In: Frontiers in Genetics. 2018 ; Vol. 9.
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abstract = "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.",
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author = "Hassan, {Syed S.} and Jamal, {Syed B.} and Radusky, {Leandro G.} and Sandeep Tiwari and Asad Ullah and Javed Ali and Behramand and {de Carvalho}, {Paulo V.S.D.} and Rida Shams and Sabir Khan and Figueiredo, {Henrique C.P.} and Debmalya Barh and Preetam Ghosh and Artur Silva and Jan Baumbach and Richard R{\"o}ttger and Turjanski, {Adri{\'a}n G.} and Azevedo, {Vasco A.C.}",
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volume = "9",
journal = "Frontiers in Genetics",
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Hassan, SS, Jamal, SB, Radusky, LG, Tiwari, S, Ullah, A, Ali, J, Behramand, de Carvalho, PVSD, Shams, R, Khan, S, Figueiredo, HCP, Barh, D, Ghosh, P, Silva, A, Baumbach, J, Röttger, R, Turjanski, AG & Azevedo, VAC 2018, 'The druggable pocketome of Corynebacterium diphtheriae: A new approach for in silico putative druggable targets' Frontiers in Genetics, vol. 9, 44. https://doi.org/10.3389/fgene.2018.00044

The druggable pocketome of Corynebacterium diphtheriae : A new approach for in silico putative druggable targets. / Hassan, Syed S.; Jamal, Syed B.; Radusky, Leandro G.; Tiwari, Sandeep; Ullah, Asad; Ali, Javed; Behramand; de Carvalho, Paulo V.S.D.; Shams, Rida; Khan, Sabir; Figueiredo, Henrique C.P.; Barh, Debmalya; Ghosh, Preetam; Silva, Artur; Baumbach, Jan; Röttger, Richard; Turjanski, Adrián G.; Azevedo, Vasco A.C.

In: Frontiers in Genetics, Vol. 9, 44, 2018.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - The druggable pocketome of Corynebacterium diphtheriae

T2 - A new approach for in silico putative druggable targets

AU - Hassan, Syed S.

AU - Jamal, Syed B.

AU - Radusky, Leandro G.

AU - Tiwari, Sandeep

AU - Ullah, Asad

AU - Ali, Javed

AU - Behramand,

AU - de Carvalho, Paulo V.S.D.

AU - Shams, Rida

AU - Khan, Sabir

AU - Figueiredo, Henrique C.P.

AU - Barh, Debmalya

AU - Ghosh, Preetam

AU - Silva, Artur

AU - Baumbach, Jan

AU - Röttger, Richard

AU - Turjanski, Adrián G.

AU - Azevedo, Vasco A.C.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Corynebacterium diphtheria

KW - Druggable genome

KW - Global druggable (GD)

KW - Highly druggable (HD)

KW - Pocketome

KW - Putative therapeutic targets

KW - Structural proteomics

U2 - 10.3389/fgene.2018.00044

DO - 10.3389/fgene.2018.00044

M3 - Journal article

VL - 9

JO - Frontiers in Genetics

JF - Frontiers in Genetics

SN - 1664-8021

M1 - 44

ER -