Understanding the structure-activity and structure-selectivity correlation of cyclic guanine derivatives as phosphodiesterase-5 inhibitors by molecular docking, CoMFA and CoMSIA analyses.
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 q(2) and conventional correlation coefficient r(2) values) for predicting the inhibitory activity against PDE5 and the selectivity against PDE6. The high q(2) and r(2) 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).
Yang
Guang-Fu
GF
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan. gfyang@mail.ccnu.edu.cn
Lu
Hai-Ting
HT
Xiong
Ying
Y
Zhan
Chang-Guo
CG
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000473:pathology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010410:Penile Erection; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
D006147:Guanine; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human