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

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

来源：Bioorganic & Medicinal Chemistry Letters, 2018, 28(13): 2239-2243.

DOI：10.1016/j.bmcl.2018.05.048

• Pathogens
• Antimicrobial resistance
• Fragment-based drug discovery
• Membrane protein
• Respiration
• NDH-2

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 mu INA 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.

• 出版日期2018-7-15