'Tethering' fragment-based drug discovery to identify inhibitors of the essential respiratory membrane protein type II NADH dehydrogenase. Issue 13 (15th July 2018) - Heikal, Adam
Graphical abstract: Highlights: 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. 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.