Drug Designing: Open Access
Open Access

Structure-based discovery of picomolar Qo site inhibitors of cytochrome bc1 complex

International Conference and Exhibition on Computer Aided Drug Design & QSAR

October 29-31, 2012 DoubleTree by Hilton Chicago-North Shore, USA

Guang-Fu Yang, Ge-Fei Hao, Fu Wang, Hui Li and Xiao-Lei Zhu

Accepted Abstracts: Drug Design

Abstract :

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 new computational protocol, called pharmacophore-linked fragment virtual screening (PFVS), was successfully developed to solve some problems in this area. This method was first applicated to yield 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) and commercial inhibitor Azoxystrobin (Ki = 297.60 nM), the most potent compound 4f displayed 20,507-fold and 6900-fold improved binding affinity (Ki = 43.00 pM) and was proved to be a non-competitive 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 � resolution, providing a molecular basis for understanding its ultra potency. To our knowledge, it was the first time of applying FBDD method in membrane protein to discover ultrahigh activity inhibitors. Furthermore, the new interaction mechanisms of these inhibitors with the surrounding residues should be valuable for future structure-based design in this area. This work also demonstrated that the novel PFVS approach was a high-throughput drug discovery method independent of biophysical screening techniques.

Biography :

Guang-Fu Yang got his Ph. D. from Nankai University in 1997. He was a visiting Professor at University of Kentucky from 2004 to 2005. He was a faculty member of Central China Normal University from 1997 and promoted as associate Professor in 1998 and Professor in 2001. Since 2002, he was selected as the Dean of College of Chemistry and the director of Key Laboratory of Pesticide & Chemical Biology of Ministry of Education. In 2009, he was awarded the National Science Foundation for Distinguished Young Scientist from NSFC. His research interests include rational design of pesticide and its chemical biology.