Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex.
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 Q(o) site inhibitors of the cytochrome bc(1) complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K(i) = 881.80 nM, porcine bc(1)), the most potent compound 4f displayed 20 507-fold improved binding affinity (K(i) = 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 (K(i) = 83.00 pM) bound to the chicken bc(1) 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.
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
Ge-Fei
GF
Hao
Fu
F
Wang
Hui
H
Li
Xiao-Lei
XL
Zhu
Wen-Chao
WC
Yang
Li-Shar
LS
Huang
Jia-Wei
JW
Wu
Edward A
EA
Berry
Guang-Fu
GF
Yang
D000818:Animals; D002645:Chickens; D018360:Crystallography, X-Ray; D015195:Drug Design; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013552:Swine; D013816:Thermodynamics
D054852:Small Molecule Libraries; D014450:Electron Transport Complex III