Pharmacophoric Pattern Analysis for β-Carboline-Based Inhibitors of Phosphodieasterase type 5 using 3D-QSAR approach

• Main Authors: Hsing-Yu Chen, 陳星佑
• Other Authors: Ping-Chiang Lyu
• Format: Others
• Language: en_US
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/20024345961045694358

碩士 === 國立清華大學 === 生物資訊與結構生物研究所 === 93 === Phosphodiesterase type 5 (PDE5) is an important enzyme for controlling the levels of the intracellular cGMP which significantly corresponds to male erection dysfunction. Tadalafil, also known as Cialis, is a β-carboline derivative which inhibits PDE5 specifically. Three-dimensional quantitative structure-activity relationship (3D-QSAR) approach was used to construct pharmacophore models for a series of β-carboline derivative inhibitors of PDE5. The models generated using Catalyst and CoMFA packages with a training set of 31 molecules were confirmed by the test set of 21 molecules. The high r2 value (0.816) between the predicted and observed activity showed that the Catalyst pharmacophore hypothesis was predictive. This hypothesis contained four features, including a hydrogen bond donor, two hydrogen bond acceptors and a hydrophobic feature. The CoMFA model consisted of four components with an r2 of 0.945 and produced good predictions for test set (r2 = 0.810). Comparison between these two models, two hydrogen bond acceptors and one hydrogen bond donor were found to contribute significantly to the inhibition activities of β-carboline derivatives. LigBuilder package was used to establish a new drug library. Totally 200 compounds were generated and rescored by using 3D-QSAR models and two scoring functions, SCORE and AutoDock. Eleven drugs were selected and thought as candidates for further analysis because of ranked among top fifty for at least three rescoring functions. PDE5-Drug Development Database (PDE5-DDDB) has been built up as a friendly platform for study of PDE5-inhibitor interactions, which archives information of new drugs.