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

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

Author information

1
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: adam.heikal@farmasi.uio.no.
2
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
3
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand.
4
Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA 94143, United States.
5
School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
6
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
7
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
8
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: greg.cook@otago.ac.nz.

Abstract

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

PMID:
29859905
DOI:
10.1016/j.bmcl.2018.05.048
[Indexed for MEDLINE]

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