Molecular docking and 3D-QSAR analyses were performed to understand how PDE5 and PDE6 interact with a series of (49) cyclic guanine derivatives. Using the conformations of the compounds revealed by molecular docking, CoMFA and CoMSIA analyses resulted in the first quantitative structure-activity relationship (QSAR) and first quantitative structure-selectivity relationship (QSSR) models (with high cross-validated correlation coefficient q2 and conventional correlation coefficient r2 values) for predicting the inhibitory activity against PDE5 and the selectivity against PDE6. The high q2 and r2 values, along with further testing, indicate that the obtained 3D-QSAR and 3D-QSSR models will be valuable in predicting both the inhibitory activity and selectivity of cyclic guanine derivatives for these protein targets. A set of 3D contour plots drawn based on the 3D-QSAR and 3D-QSSR models reveal some useful clues to improve both the activity and selectivity by modifying structures of the compounds. It has been demonstrated that both the steric and electrostatic factors should appropriately be taken into account in future rational design and development of more active and more selective PDE5 inhibitors for the therapeutic treatment of erectile dysfunction (ED).
|Number of pages||12|
|Journal||Bioorganic and Medicinal Chemistry|
|State||Published - Mar 1 2006|
Bibliographical noteFunding Information:
This research was supported by the College of Pharmacy and the Center for Computational Sciences (CCS) at University of Kentucky. The work was performed when GFY worked in CGZ’s laboratory at University of Kentucky as a visiting scientist. The authors acknowledge CCS at University of Kentucky for supercomputing time on Superdome (a shared-memory supercomputer, with 4 nodes and 256 processors).
- Binding mode
- Selective inhibition
- Structure-activity correlation
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry