Key Features for Designing Phosphodiesterase-5 Inhibitors

Abstract

Phosphodiesterase superfamily is the key regulator of 3',5'-cyclic guanosine monophosphate (cGMP) decomposition in human body. Phosphodiesterase-5 (PDE-5) inhibitors, sildenafil, vardenafil and tadalafil, are well known oral treatment for males with erectile dysfunction. To investigate the inhibitory effects of traditional Chinese medicine (TCM) compounds to PDE-5, we performed both ligand-based and structure-based studies on this topic. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted to construct three dimensional quantitative structure-activity relationship (3D-QSAR) models of series of known PDE-5 inhibitors. The predictive models had cross-validated, q(2), and non cross-validated coefficient, r(2), values of 0.791 and 0.948 for CoMFA and 0.724 and 0.908 for CoMSIA. These two 3D-QSAR models were used to predict activity of TCM compounds. Docking simulations were performed to further analyze the binding mode of training set and TCM compounds. A putative binding model was proposed based on CoMFA and CoMSIA contour maps and docking simulations; formation of pi-stacking, water bridge and specific hydrogen bonding were deemed important interactions between ligands and PDE-5. Of our TCM compounds, engeletin, satisfied our binding model, and hence, emerged as PDE-5 inhibitor candidate. Using this study as an example, we demonstrated that docking should be conducted for qualitative purposes, such as identifying protein characteristics, rather than for quantitative analyses that rank compound efficacy based on results of scoring functions. Prediction of compound activity should be reserved for QSAR analyses, and scoring functions and docking scores should be used for preliminary screening of TCM database (http://tcm.cmu.edu.tw/index.php).

Drug design for hemagglutinin: Screening and molecular dynamics from traditional Chinese medicine database

“…different topics (Bhargavi et al, 2010;Cambria et al, 2010;Cao and Wang, 2010;Chang et al, 2010;Chen, 2010;da Cunha et al, 2010;Huang et al, 2010a,b;Kahlon et al, 2010;Koshy et al, 2010). Previously, we had conduced in silico studies on influenza hemagglutinin (Chen et al, 2009a.…”

Inhibition of mushroom tyrosinase by a newly synthesized ligand: inhibition kinetics and computational simulations

“…Currently, there is a great deal of interest in drug design investigations involving ligand and protein interactions and different theoretical methodologies have been applied to the drug design in a variety of biological systems and there have been extensive publications in this journal (Banappagari, Ronald, & Satyanarayanajois, 2010;Cambria, Di Marino, Falconi, Garavaglia, & Cambria, 2010;Chang et al, 2010;da Cunha, Barbosa, Oliveira, & Ramalho, 2010;Huang et al, 2010;Kahlon, Roy, & Sharma, 2010;Nasiri, Bahrami, Zahedi, Moosavi-Movahedi, & Sattarahmady, 2010;Nekrasov & Zinchenko, 2010;Ompraba, Velmurugan, Louis, & Rafi, 2010;Ramalho, Rocha, da Cunha, Oliveira, & Carvalho, 2010;Tao, Rao, & Liu, 2010;Yang et al, 2010).…”

iScreen: world’s first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan

“…For thousands of years, TCM has become a vast knowledge bank of medicine [1][2][3][4][5][6][7]. As more bioactive compounds isolated from TCM, a comprehensive drug design operating platform is required for systematically analyzing the therapeutic values of the TCM components.…”