title: Inhibition of NarL of Mycobacterium Tuberculosis: an in silico approach.
abstract: Mycobacterium tuberculosis (MTB) consumes nitrate as the alternate mechanism of respiration in the absence of oxygen, thus increasing its survival and virulence during latent stage of tuberculosis infection. NarL is a nitrate/nitrite response transcriptional regulatory protein of two-component signal transduction system which regulates nitrate reductase and formate dehydrogenase for MTB adaptation to anaerobic condition. Phosphorylation by sensor kinase (NarX) is the primary mechanism behind the activation of NarL although many response regulators get activated by small molecule phospho-donors in the absence of sensor kinase. Virtual screening was performed using Autodock suite for the compounds from ZINC database against NarL and potential inhibitors was identified to inhibit the activation of NarL by affecting its phosphorylation. Molecular dynamics simulation studies predicted the stability of 1-{1-[(3-nitrophenyl) methyl] piperidin-2-yl} ethan-1-amine in the active site of NarL over 10 ns simulation. Phosphorylation of NarL by small molecule phospho-donors is also investigated in the present study. Here we suggest that nitro benzene - amine piperidine moiety can be an effective lead candidate for developing novel anti-tuberculosis drugs.
authors.affiliation: Department of Biotechnology, PES Institute of Technology, BSK III stage, Bangalore, 560085, India.
authors.forename: K V
authors.initials: KV
authors.lastname: Shivakumar
authors.forename: Prashantha
authors.initials: P
authors.lastname: Karunakar
authors.forename: Jhinuk
authors.initials: J
authors.lastname: Chatterjee
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D005560:Formate Dehydrogenases / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D009565:Nitrate Reductases / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D009584:Nitrogen / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D009566:Nitrates; D009573:Nitrites; D009578:Nitrobenzenes; D010880:Piperidines; D014157:Transcription Factors; C032727:piperidine; C036077:nitrobenzene; D005560:Formate Dehydrogenases; D009565:Nitrate Reductases; D011494:Protein Kinases; D009584:Nitrogen