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

Adam Heikal; Yoshio Nakatani; Wanting Jiao; Chris Wilson; David Rennison; Marion R Weimar; Emily J Parker; Margaret A Brimble; Gregory M Cook

doi:10.1016/j.bmcl.2018.05.048

'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.

Authors

Adam Heikal¹, Yoshio Nakatani², Wanting Jiao³, Chris Wilson⁴, David Rennison⁵, Marion R Weimar⁶, Emily J Parker³, Margaret A Brimble⁷, Gregory M Cook⁸

Affiliations

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.

PMID: 29859905
DOI: 10.1016/j.bmcl.2018.05.048

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.

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

Substances

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