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.
N1 - Publisher Copyright:
© 2018 Hassan, Jamal, Radusky, Tiwari, Ullah, Ali, Behramand, de Carvalho, Shams, Khan, Figueiredo, Barh, Ghosh, Silva, Baumbach, Röttger, Turjanski and Azevedo.
PY - 2018/2/13
Y1 - 2018/2/13
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
UR - http://www.scopus.com/inward/record.url?scp=85042412394&partnerID=8YFLogxK
U2 - 10.3389/fgene.2018.00044
DO - 10.3389/fgene.2018.00044
M3 - Article
AN - SCOPUS:85042412394
SN - 1664-8021
VL - 9
JO - Frontiers in Genetics
JF - Frontiers in Genetics
IS - FEB
M1 - 44
ER -