title: Identification of Phosphoribosyl-AMP cyclohydrolase, as drug target and its inhibitors in Brucella melitensis bv. 1 16M using metabolic pathway analysis.
abstract: Brucella melitensis is a pathogenic Gram-negative bacterium which is known for causing zoonotic diseases (Brucellosis). The organism is highly contagious and has been reported to be used as bioterrorism agent against humans. Several antibiotics and vaccines have been developed but these antibiotics have exhibited the sign of antibiotic resistance or ineffective at lower concentrations, which imposes an urgent need to identify the novel drugs/drug targets against this organism. In this work, metabolic pathways analysis has been performed with different filters such as non-homology with humans, essentially of genes and choke point analysis, leading to identification of novel drug targets. A total of 18 potential drug target proteins were filtered out and used to develop the high confidence protein-protein interaction network The Phosphoribosyl-AMP cyclohydrolase (HisI) protein has been identified as potential drug target on the basis of topological parameters. Further, a homology model of (HisI) protein has been developed using Modeller with multiple template (1W6Q (48%), 1ZPS (55%), and 2ZKN (48%)) approach and validated using PROCHECK and Verify3D. The virtual high throughput screening (vHTS) using DockBlaster tool has been performed against 16,11,889 clean fragments from ZINC database. Top 500 molecules from DockBlaster were docked using Vina. The docking analysis resulted in ZINC04880153 showing the lowest binding energy (-9.1 kcal/mol) with the drug target. The molecular dynamics study of the complex HisI-ZINC04880153 was conducted to analyze the stability and fluctuation of ligand within the binding pocket of HisI. The identified ligand could be analyzed in the wet-lab based experiments for future drug discovery.
authors.affiliation: a Department of Biotechnology , Jaypee Institute of Information Technology , A-10, Sector-62, Noida , Uttar Pradesh 201307 , India.
authors.forename: Money
authors.initials: M
authors.lastname: Gupta
authors.affiliation: b Department of Computer Science and Engineering , Indian Institute of Technology Delhi , New Delhi 110016 , India.
authors.forename: Yamuna
authors.initials: Y
authors.lastname: Prasad
authors.affiliation: a Department of Biotechnology , Jaypee Institute of Information Technology , A-10, Sector-62, Noida , Uttar Pradesh 201307 , India.
authors.forename: Sanjeev Kumar
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: a Department of Biotechnology , Jaypee Institute of Information Technology , A-10, Sector-62, Noida , Uttar Pradesh 201307 , India.
authors.forename: Chakresh Kumar
authors.initials: CK
authors.lastname: Jain
mesh_terms: D000619:Aminohydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D017347:Brucella melitensis / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D053858:Metabolic Networks and Pathways; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D000619:Aminohydrolases; C022383:phosphoribosyl-AMP cyclohydrolase
keywords: Brucella melitensis; HisI; drug target; metabolic proteins; molecular dynamics simulations