title: In silico approach towards identification of potential inhibitors of Helicobacter pylori DapE.
abstract: Helicobacter pylori is a gastric mucosal pathogen and is associated with diseases like peptic ulcer and gastric cancer. To combat H. pylori infection, there is an urgent need for new class of antibiotics due to the emergence of drug-resistant strains. Enzymes involved in bacterial lysine biosynthetic pathways may be potential targets for antibacterial drug development, since lysine is an essential component of the bacterial peptidoglycan cell wall. No pathway exists for lysine biosynthesis in humans; hence, the inhibitors targeting bacterial enzymes may have selective toxicity. dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a critical enzyme of this pathway and deletion of DapE gene is lethal to H. pylori, since the organism has no alternative pathway for lysine biosynthesis. In this study, we reported a 3D model structure of H. pylorie DapE, which consisted of a catalytic domain and a dimerization domain generated by MODELLER software. We also confirmed the stability of the modeled structure through 10 ns molecular dynamics simulation using GROMACS software. Next, to identify potential small molecule inhibitors of DapE, drug-like small molecule-screening library was generated. This was performed by Tanimoto-based similarity searching in the PubChem Database with DapE substrate L,L-SDAP as a query molecule, followed by fragment-based docking approach using GLIDE XP. This approach identified two potential substrate-competitive small molecule inhibitors of DapE. These new molecules may provide a starting point to search for novel therapeutics.
authors.affiliation: a Biomedical Informatics Centre, National Institute of Cholera and Enteric Diseases , P-33, C.I.T. Road, Scheme XM, Beleghata, Kolkata 700 010 , India.
authors.forename: Rahul Shubhra
authors.initials: RS
authors.lastname: Mandal
authors.forename: Santasabuj
authors.initials: S
authors.lastname: Das
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016480:Helicobacter pylori / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D015203:Reproducibility of Results; D016415:Sequence Alignment; D054852:Small Molecule Libraries; D013379:Substrate Specificity
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries
keywords: DapE; Helicobacter pylori; fragment docking; homology modeling; inhibitor