TY - JOUR
T1 - An integrative in-silico approach for therapeutic target identification in the human pathogen Corynebacterium diphtheriae
AU - Jamal, Syed Babar
AU - Hassan, Syed Shah
AU - Tiwari, Sandeep
AU - Viana, Marcus V.
AU - De Jesus Benevides, Leandro
AU - Ullah, Asad
AU - Turjanski, Adrián G.
AU - Barh, Debmalya
AU - Ghosh, Preetam
AU - Costa, Daniela Arruda
AU - Silva, Artur
AU - Röttger, Richard
AU - Baumbach, Jan
AU - Azevedo, Vasco A.C.
N1 - Publisher Copyright:
© 2017, Public Library of Science. All rights reserved. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2017/10
Y1 - 2017/10
N2 - Corynebacterium diphtheriae (Cd) is a Gram-positive human pathogen responsible for diphtheria infection and once regarded for high mortalities worldwide. The fatality gradually decreased with improved living standards and further alleviated when many immunization programs were introduced. However, numerous drug-resistant strains emerged recently that consequently decreased the efficacy of current therapeutics and vaccines, thereby obliging the scientific community to start investigating new therapeutic targets in pathogenic microorganisms. In this study, our contributions include the prediction of modelome of 13 C. diphtheriae strains, using the MHOLline workflow. A set of 463 conserved proteins were identified by combining the results of pangenomics based core-genome and core-modelome analyses. Further, using subtractive proteomics and modelomics approaches for target identification, a set of 23 proteins was selected as essential for the bacteria. Considering human as a host, eight of these proteins (glpX, nusB, rpsH, hisE, smpB, bioB, DIP1084, and DIP0983) were considered as essential and non-host homologs, and have been subjected to virtual screening using four different compound libraries (extracted from the ZINC database, plant-derived natural compounds and Di-terpenoid Iso-steviol derivatives). The proposed ligand molecules showed favorable interactions, lowered energy values and high complementarity with the predicted targets. Our proposed approach expedites the selection of C. diphtheriae putative proteins for broad-spectrum development of novel drugs and vaccines, owing to the fact that some of these targets have already been identified and validated in other organisms.
AB - Corynebacterium diphtheriae (Cd) is a Gram-positive human pathogen responsible for diphtheria infection and once regarded for high mortalities worldwide. The fatality gradually decreased with improved living standards and further alleviated when many immunization programs were introduced. However, numerous drug-resistant strains emerged recently that consequently decreased the efficacy of current therapeutics and vaccines, thereby obliging the scientific community to start investigating new therapeutic targets in pathogenic microorganisms. In this study, our contributions include the prediction of modelome of 13 C. diphtheriae strains, using the MHOLline workflow. A set of 463 conserved proteins were identified by combining the results of pangenomics based core-genome and core-modelome analyses. Further, using subtractive proteomics and modelomics approaches for target identification, a set of 23 proteins was selected as essential for the bacteria. Considering human as a host, eight of these proteins (glpX, nusB, rpsH, hisE, smpB, bioB, DIP1084, and DIP0983) were considered as essential and non-host homologs, and have been subjected to virtual screening using four different compound libraries (extracted from the ZINC database, plant-derived natural compounds and Di-terpenoid Iso-steviol derivatives). The proposed ligand molecules showed favorable interactions, lowered energy values and high complementarity with the predicted targets. Our proposed approach expedites the selection of C. diphtheriae putative proteins for broad-spectrum development of novel drugs and vaccines, owing to the fact that some of these targets have already been identified and validated in other organisms.
UR - http://www.scopus.com/inward/record.url?scp=85031735924&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0186401
DO - 10.1371/journal.pone.0186401
M3 - Article
C2 - 29049350
AN - SCOPUS:85031735924
SN - 1932-6203
VL - 12
JO - PLoS ONE
JF - PLoS ONE
IS - 10
M1 - e0186401
ER -