title: Proteome scale comparative modeling for conserved drug and vaccine targets identification in Corynebacterium pseudotuberculosis.
abstract: Corynebacterium pseudotuberculosis (Cp) is a pathogenic bacterium that causes caseous lymphadenitis (CLA), ulcerative lymphangitis, mastitis, and edematous to a broad spectrum of hosts, including ruminants, thereby threatening economic and dairy industries worldwide. Currently there is no effective drug or vaccine available against Cp. To identify new targets, we adopted a novel integrative strategy, which began with the prediction of the modelome (tridimensional protein structures for the proteome of an organism, generated through comparative modeling) for 15 previously sequenced C. pseudotuberculosis strains. This pan-modelomics approach identified a set of 331 conserved proteins having 95-100% intra-species sequence similarity. Next, we combined subtractive proteomics and modelomics to reveal a set of 10 Cp proteins, which may be essential for the bacteria. Of these, 4 proteins (tcsR, mtrA, nrdI, and ispH) were essential and non-host homologs (considering man, horse, cow and sheep as hosts) and satisfied all criteria of being putative targets. Additionally, we subjected these 4 proteins to virtual screening of a drug-like compound library. In all cases, molecules predicted to form favorable interactions and which showed high complementarity to the target were found among the top ranking compounds. The remaining 6 essential proteins (adk, gapA, glyA, fumC, gnd, and aspA) have homologs in the host proteomes. Their active site cavities were compared to the respective cavities in host proteins. We propose that some of these proteins can be selectively targeted using structure-based drug design approaches (SBDD). Our results facilitate the selection of C. pseudotuberculosis putative proteins for developing broad-spectrum novel drugs and vaccines. A few of the targets identified here have been validated in other microorganisms, suggesting that our modelome strategy is effective and can also be applicable to other pathogens.
authors.forename: Syed Shah
authors.initials: SS
authors.lastname: Hassan
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tiwari
authors.forename: Luís Carlos
authors.initials: LC
authors.lastname: Guimarães
authors.forename: Syed Babar
authors.initials: SB
authors.lastname: Jamal
authors.forename: Edson
authors.initials: E
authors.lastname: Folador
authors.forename: Neha Barve
authors.initials: NB
authors.lastname: Sharma
authors.forename: Siomar
authors.initials: S
authors.lastname: de Castro Soares
authors.forename: Síntia
authors.initials: S
authors.lastname: Almeida
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Arshad
authors.initials: A
authors.lastname: Islam
authors.forename: Fabiana Dias
authors.initials: FD
authors.lastname: Póvoa
authors.forename: Vinicius Augusto Carvalho
authors.initials: VA
authors.lastname: de Abreu
authors.forename: Neha
authors.initials: N
authors.lastname: Jain
authors.forename: Antaripa
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Lucky
authors.initials: L
authors.lastname: Juneja
authors.forename: Anderson
authors.initials: A
authors.lastname: Miyoshi
authors.forename: Artur
authors.initials: A
authors.lastname: Silva
authors.forename: Debmalya
authors.initials: D
authors.lastname: Barh
authors.forename: Adrian  Gustavo
authors.initials: A
authors.lastname: Turjanski
authors.forename: Vasco
authors.initials: V
authors.lastname: Azevedo
authors.forename: Rafaela Salgado
authors.initials: RS
authors.lastname: Ferreira
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D001428:Bacterial Vaccines; D019295:Computational Biology; D003198:Computer Simulation; D017124:Conserved Sequence; D016925:Corynebacterium pseudotuberculosis / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D020043:Genes, Essential; D006801:Humans; D020543:Proteome / Q000235:genetics*; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D020543:Proteome