title: An Approach for Identification of Novel Drug Targets in Streptococcus pyogenes SF370 Through Pathway Analysis.
abstract: Streptococcus pyogenes is one of the most important pathogens as it is involved in various infections affecting upper respiratory tract and skin. Due to the emergence of multidrug resistance and cross-resistance, S. Pyogenes is becoming more pathogenic and dangerous. In the present study, an in silico comparative analysis of total 65 metabolic pathways of the host (Homo sapiens) and the pathogen was performed. Initially, 486 paralogous enzymes were identified so that they can be removed from possible drug target list. The 105 enzymes of the biochemical pathways of S. pyogenes from the KEGG metabolic pathway database were compared with the proteins from the Homo sapiens by performing a BLASTP search against the non-redundant database restricted to the Homo sapiens subset. Out of these, 83 enzymes were identified as non-human homologous while 30 enzymes of inadequate amino acid length were removed for further processing. Essential enzymes were finally mined from remaining 53 enzymes. Finally, 28 essential enzymes were identified in S. pyogenes SF370 (serotype M1). In subcellular localization study, 18 enzymes were predicted with cytoplasmic localization and ten enzymes with the membrane localization. These ten enzymes with putative membrane localization should be of particular interest. Acyl-carrier-protein S-malonyltransferase, DNA polymerase III subunit beta and dihydropteroate synthase are novel drug targets and thus can be used to design potential inhibitors against S. pyogenes infection. 3D structure of dihydropteroate synthase was modeled and validated that can be used for virtual screening and interaction study of potential inhibitors with the target enzyme.
authors.affiliation: Department of Computational Biology and Bioinformatics, SHIATS, Allahabad, 211007, India.
authors.forename: Satendra
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Biotechnology, Institute of Biosciences and Biotechnology, Chhatrapati Shahu Ji Maharaj University, Kanpur, 208024, India. answer.dev@gmail.com.
authors.forename: Dev Bukhsh
authors.initials: DB
authors.lastname: Singh
authors.affiliation: Maitreyi College, University of Delhi, Delhi, India.
authors.forename: Anamika
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Computational Biology and Bioinformatics, SHIATS, Allahabad, 211007, India.
authors.forename: Budhayash
authors.initials: B
authors.lastname: Gautam
authors.affiliation: Department of Molecular and Cellular Engineering, SHIATS, Allahabad, 211007, India.
authors.forename: Gurudayal
authors.initials: G
authors.lastname: Ram
authors.affiliation: School of Biotechnology, Gautam Buddha University, Greater Noida, 201308, Uttar Pradesh, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Dwivedi
authors.affiliation: Department of Biological Sciences, SHIATS, Allahabad, 211007, India.
authors.forename: Pramod W
authors.initials: PW
authors.lastname: Ramteke
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004094:Dihydropteroate Synthase / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D004094:Dihydropteroate Synthase
keywords: Drug targets; Inhibitors; Metabolic pathway; Model validation; Paralogous enzymes; S. pyogenes