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

• Published in: Bioorganic & medicinal chemistry letters 2018-07, Vol.28 (13), p.2239-2243
• Main Authors: Heikal, Adam, Nakatani, Yoshio, Jiao, Wanting, Wilson, Chris, Rennison, David, Weimar, Marion R., Parker, Emily J., Brimble, Margaret A., Cook, Gregory M.
• Format: Article
• Language: English
• Subjects: Antimicrobial resistance; 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; Fragment-based drug discovery; Membrane protein; 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; NDH-2; Pathogens; Protein Binding; Respiration
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.05.048

[Display omitted] •Type II NADH dehydrogenase remains a promising but challenging antimicrobial target.•Tethering-fragment based drug design is a site-directed screening technique.•Cysteine-engineered mutants allow targeting of quinone catalytic site.•Inhibitory fragments identified by screening di-sulfide containing compound library.•In silico docking reveals possible fragment binding poses. 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.