title: An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets.
abstract: BACKGROUND
  The bacterium Corynebacterium pseudotuberculosis (Cp) causes caseous lymphadenitis (CLA), mastitis, ulcerative lymphangitis, and oedema in a number of hosts, comprising ruminants, thereby intimidating economic and dairy industries worldwide. So far there is no effective drug or vaccine available against Cp. Previously, a pan-genomic analysis was performed for both biovar equi and biovar ovis and a Pathogenicity Islands (PAIS) analysis within the strains highlighted a large set of proteins that could be relevant therapeutic targets for controlling the onset of CLA. In the present work, a structural druggability analysis pipeline was accomplished along 15 previously sequenced Cp strains from both biovar equi and biovar ovis.
  
  
  RESULTS
  We computed the whole modelome of a reference strain Cp1002 (NCBI Accession: NC_017300.1) and then the homology models of proteins, of 14 different Cp strains, with high identity (≥ 85%) to the reference strain were also done. Druggability score of all proteins pockets was calculated and only those targets that have a highly druggable (HD) pocket in all strains were kept, a set of 58 proteins. Finally, this information was merged with the previous PAIS analysis giving two possible highly relevant targets to conduct drug discovery projects. Also, off-targeting information against host organisms, including Homo sapiens and a further analysis for protein essentiality provided a final set of 31 druggable, essential and non-host homologous targets, tabulated in table S4, additional file 1. Out of 31 globally druggable targets, 9 targets have already been reported in other pathogenic microorganisms, 3 of them (3-isopropylmalate dehydratase small subunit, 50S ribosomal protein L30, Chromosomal replication initiator protein DnaA) in C. pseudotuberculosis.
  
  
  CONCLUSIONS
  Overall we provide valuable information of possible targets against C. pseudotuberculosis where some of these targets have already been reported in other microorganisms for drug discovery projects, also discarding targets that might be physiologically relevant but are not amenable for drug binding. We propose that the constructed in silico dataset might serve as a guidance for the scientific community to have a better understanding while selecting putative therapeutic protein candidates as druggable ones as effective measures against C. pseudotuberculosis.
authors.forename: Leandro G
authors.initials: LG
authors.lastname: Radusky
authors.forename: Syed
authors.initials: S
authors.lastname: Hassan
authors.forename: Esteban
authors.initials: E
authors.lastname: Lanzarotti
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tiwari
authors.forename: Syed
authors.initials: S
authors.lastname: Jamal
authors.forename: Javed
authors.initials: J
authors.lastname: Ali
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Rafaela
authors.initials: R
authors.lastname: Ferreira
authors.forename: Debmalya
authors.initials: D
authors.lastname: Barh
authors.forename: Artur
authors.initials: A
authors.lastname: Silva
authors.forename: Adrián G
authors.initials: AG
authors.lastname: Turjanski
authors.forename: Vasco Ac
authors.initials: VA
authors.lastname: Azevedo
mesh_terms: D000465:Algorithms; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003354:Corynebacterium Infections / Q000188:drug therapy / Q000662:veterinary*; D016925:Corynebacterium pseudotuberculosis / Q000187:drug effects* / Q000235:genetics*; D016680:Genome, Bacterial / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016366:Open Reading Frames / Q000235:genetics; D040901:Proteomics / Q000379:methods
chemical_list: D000900:Anti-Bacterial Agents