Heikal Adam, Nakatani Yoshio, Jiao Wanting, Wilson Chris, Rennison David, Weimar Marion R, Parker Emily J, Brimble Margaret A, Cook Gregory M
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.
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.
Bioorg Med Chem Lett. 2018 Jul 15;28(13):2239-2243. doi: 10.1016/j.bmcl.2018.05.048. Epub 2018 May 26.
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 IC 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.
能量生成是细菌病原体和寄生虫药物发现的一个有前景的领域。II型NADH脱氢酶（NDH-2）是一种重要的呼吸膜蛋白，作为新型抗结核和抗疟药物开发的靶点已引起关注。然而，迄今为止，尚未鉴定出有效的特异性抑制剂。在此，我们针对含有工程化活性位点半胱氨酸的NDH-2野生型和突变体形式，进行了一种基于定点筛选技术——基于片段连接的药物发现。抑制性片段对NDH-2突变体的IC值在3至110μM之间。通过计算机模拟研究了可能的结合构象，为优化片段结合和提高对NDH-2的效力提供了基础。
