Structure-Based Rational Design of Novel Inhibitors Against Fructose-1,6-Bisphosphate Aldolase fromCandida albicans

• DOI: 10.1021/acs.jcim.6b00763
• Publication Date: 2017-05-05T16:33:26Z
• Authors: Xinya Han; Xiuyun Zhu; Zongqin Hong; Lin Wei; Yanliang Ren; Fen Wan; Shuaihua Zhu; Hao Peng; Li Guo; Li Rao; Lingling Feng; Jian Wan
• Keywords: Rational design; Fructose 2,6-bisphosphate

Class II fructose-1,6-bisphosphate aldolases (FBA-II) are attractive new targets for the discovery of drugs to combat invasive fungal infection, because they absent in animals and higher plants. Although several FBA-II inhibitors have been reported, none these exhibit antifungal effect so far. In this study, novel from C. albicans (Ca-FBA-II) with potent effects were rationally designed by jointly using a specific protocols molecular docking-based virtual screening, accurate binding-conformation evaluation strategy, synthesis enzymatic assays. The assays reveal that compounds 3c, 3e–g, 3j 3k high inhibitory activity against Ca-FBA-II (IC50 < 10 μM), most potential inhibitor is 3g, IC50 value 2.7 μM. Importantly, 3f, 3l possess not only inhibitions Ca-FBA-II, but also moderate activities glabrata (MIC80 = 4–64 μg/mL). 3l, combination fluconazole (8 μg/mL) displayed significantly synergistic 0.0625 resistant Candida strains, which azoles drugs. probable binding modes between 3g active site proposed DOX (docking, ONIOM, XO) strategy. To our knowledge, no wild type strains reported previously. positive results suggest strategy adopted study promising method azole-resistant pathogens future.