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Computational Discovery of Picomolar Qo Site Inhibitors of Cytochrome bc1 Complex

Hao, Ge-Fei, Wang, Fu, Li, Hui, Zhu, Xiao-Lei, Yang, Wen-Chao, Huang, Li-Shar, Wu, Jia-Wei, Berry, Edward A., Yang, Guang-Fu
Journal of the American Chemical Society 2012 v.134 no.27 pp. 11168-11176
binding capacity, chickens, crystal structure, cytochrome c, drugs, fungicides, membrane proteins, screening, swine, ubiquinol-cytochrome-c reductase
A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Qₒ site inhibitors of the cytochrome bc₁ complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (Kᵢ = 881.80 nM, porcine bc₁), the most potent compound 4f displayed 20 507-fold improved binding affinity (Kᵢ = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (Kᵢ = 83.00 pM) bound to the chicken bc₁ at 2.70 Å resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques.