'Tethering' fragment-based drug discovery to identify inhibitors of the essential respiratory membrane protein type II NADH dehydrogenase

Bioorg Med Chem Lett. 2018 Jul 15;28(13):2239-2243. doi: 10.1016/j.bmcl.2018.05.048. Epub 2018 May 26.


Energy generation is a promising area of drug discovery for both bacterial pathogens and parasites. Type II NADH dehydrogenase (NDH-2), a vital respiratory membrane protein, has attracted attention as a target for the development of new antitubercular and antimalarial agents. To date, however, no potent, specific inhibitors have been identified. Here, we performed a site-directed screening technique, tethering-fragment based drug discovery, against wild-type and mutant forms of NDH-2 containing engineered active-site cysteines. Inhibitory fragments displayed IC50 values between 3 and 110 μM against NDH-2 mutants. Possible binding poses were investigated by in silico modelling, providing a basis for optimisation of fragment binding and improved potency against NDH-2.

Keywords: Antimicrobial resistance; Fragment-based drug discovery; Membrane protein; NDH-2; Pathogens; Respiration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacillaceae / enzymology
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Binding Sites
  • Cysteine / chemistry
  • Cysteine / genetics
  • Drug Design*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Molecular Docking Simulation
  • Mutagenesis, Site-Directed
  • Mutation
  • NADH Dehydrogenase / antagonists & inhibitors
  • NADH Dehydrogenase / chemistry
  • NADH Dehydrogenase / genetics
  • NADH Dehydrogenase / metabolism*
  • Protein Binding


  • Bacterial Proteins
  • Enzyme Inhibitors
  • Membrane Proteins
  • NADH dehydrogenase II
  • NADH Dehydrogenase
  • Cysteine