Artículos de revistas
The Druggable Pocketome of Corynebacterium diphtheriae: A New Approach for in silico Putative Druggable Targets
Fecha
2018-02-13Registro en:
Frontiers In Genetics. Lausanne: Frontiers Media Sa, v. 9, 9 p., 2018.
1664-8021
10.3389/fgene.2018.00044
WOS:000424928000001
WOS000424928000001.pdf
Autor
Islamia Coll Univ Peshawar
Universidade Federal de Minas Gerais (UFMG)
Univ Buenos Aires
Kohat Univ Sci & Technol
Universidade Estadual Paulista (Unesp)
Inst Integrat Omics & Appl Biotechnol
Virginia Commonwealth Univ
Fed Univ Para
Univ Southern Denmark
Institución
Resumen
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 (similar to 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.
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