An integrative in-silico approach for therapeutic target identification in the human pathogen Corynebacterium diphtheriae

Syed Babar Jamal, Syed Shah Hassan, Sandeep Tiwari, Marcus V. Viana, Leandro De Jesus Benevides, Asad Ullah, Adrián G. Turjanski, Debmalya Barh, Preetam Ghosh, Daniela Arruda Costa, Artur Silva, Richard Röttger, Jan Baumbach, Vasco A.C. Azevedo

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Abstract

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.

Original languageEnglish
Article numbere0186401
JournalPLOS ONE
Volume12
Issue number10
Number of pages25
ISSN1932-6203
DOIs
Publication statusPublished - 2017

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Corynebacterium diphtheriae
Forensic Anthropology
Pathogens
Computer Simulation
therapeutics
pathogens
Proteins
Vaccines
proteins
steviol
vaccines
Immunization
drugs
Immunization Programs
Diphtheria
Workflow
Terpenes
terpenoids
Pharmaceutical Preparations
Microorganisms

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Jamal, S. B., Hassan, S. S., Tiwari, S., Viana, M. V., De Jesus Benevides, L., Ullah, A., ... Azevedo, V. A. C. (2017). An integrative in-silico approach for therapeutic target identification in the human pathogen Corynebacterium diphtheriae. PLOS ONE, 12(10), [e0186401]. https://doi.org/10.1371/journal.pone.0186401
Jamal, Syed Babar ; Hassan, Syed Shah ; Tiwari, Sandeep ; Viana, Marcus V. ; De Jesus Benevides, Leandro ; Ullah, Asad ; Turjanski, Adrián G. ; Barh, Debmalya ; Ghosh, Preetam ; Costa, Daniela Arruda ; Silva, Artur ; Röttger, Richard ; Baumbach, Jan ; Azevedo, Vasco A.C. / An integrative in-silico approach for therapeutic target identification in the human pathogen Corynebacterium diphtheriae. In: PLOS ONE. 2017 ; Vol. 12, No. 10.
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title = "An integrative in-silico approach for therapeutic target identification in the human pathogen Corynebacterium diphtheriae",
abstract = "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.",
author = "Jamal, {Syed Babar} and Hassan, {Syed Shah} and Sandeep Tiwari and Viana, {Marcus V.} and {De Jesus Benevides}, Leandro and Asad Ullah and Turjanski, {Adri{\'a}n G.} and Debmalya Barh and Preetam Ghosh and Costa, {Daniela Arruda} and Artur Silva and Richard R{\"o}ttger and Jan Baumbach and Azevedo, {Vasco A.C.}",
year = "2017",
doi = "10.1371/journal.pone.0186401",
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Jamal, SB, Hassan, SS, Tiwari, S, Viana, MV, De Jesus Benevides, L, Ullah, A, Turjanski, AG, Barh, D, Ghosh, P, Costa, DA, Silva, A, Röttger, R, Baumbach, J & Azevedo, VAC 2017, 'An integrative in-silico approach for therapeutic target identification in the human pathogen Corynebacterium diphtheriae' PLOS ONE, vol. 12, no. 10, e0186401. https://doi.org/10.1371/journal.pone.0186401

An integrative in-silico approach for therapeutic target identification in the human pathogen Corynebacterium diphtheriae. / Jamal, Syed Babar; Hassan, Syed Shah; Tiwari, Sandeep; Viana, Marcus V.; De Jesus Benevides, Leandro; Ullah, Asad; Turjanski, Adrián G.; Barh, Debmalya; Ghosh, Preetam; Costa, Daniela Arruda; Silva, Artur; Röttger, Richard; Baumbach, Jan; Azevedo, Vasco A.C.

In: PLOS ONE, Vol. 12, No. 10, e0186401, 2017.

Research output: Contribution to journalJournal articleResearchpeer-review

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.

PY - 2017

Y1 - 2017

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.

U2 - 10.1371/journal.pone.0186401

DO - 10.1371/journal.pone.0186401

M3 - Journal article

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SN - 1932-6203

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ER -