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Journal ArticleDOI

Docking-based 3D-QSAR Studies of Phosphodiesterase 9A Inhibitors

31 Aug 2017-Letters in Drug Design & Discovery-Vol. 14, Iss: 9, pp 986-998
About: This article is published in Letters in Drug Design & Discovery.The article was published on 2017-08-31. It has received 3 citations till now. The article focuses on the topics: Docking (molecular).
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TL;DR: Analysis of the receptor-based CoMFA and CoMSIA-SE contour maps provided much helpful information to improve the bioactivities of aryl-chromeno-pyrrol analogs as PDE5 inhibitors.
Abstract: Phosphodiesterase-5 (PDE5) inhibitors can be used as clinical agents for the treatment of erectile dysfunction and pulmonary hypertension. A series of aryl-chromeno-pyrrol derivatives were previously identified as PDE5 inhibitors in our lab. Herein, these molecules were subjected to 3D-QSAR analysis with CoMFA and CoMSIA methods to gain deeper insight into the structural requirements for their bioactivities. Receptor- and ligand-based alignment were used and compared to find the alignment-related factors that affect the accuracy of QSAR models. The receptor-based CoMFA and CoMSIA models, which were generated by superimposing the docking conformations directly in the protein binding site, gave more significant results for 38 training set compounds and 5 test set molecules. Comparison of the two alignments revealed that spatial arrangement of the ligands is the principal factor in determining the reliability of the 3D-QSAR models. Detailed analysis of the receptor-based CoMSIA-SE contour maps provided much helpful information to improve the bioactivities of aryl-chromeno-pyrrol analogs as PDE5 inhibitors.

1 citations


Cites methods from "Docking-based 3D-QSAR Studies of Ph..."

  • ...By introducing receptor information during the alignment process, the so called receptor-based 3D-QSAR analysis, which uses the receptor bound ligands for model generation, has been proved to be more reliable (Zheng et al., 2016; Zheng et al., 2017; Tan et al., 2017)....

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  • ...In an earlier work, a remarkably higher cross-validated q2 and the conventional r2 values were obtained from a training set of 123 PDE9 agents using RBA method, compared with LBA method (Tan et al., 2017)....

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  • ...Apparently, only RBA produced a significant CoMFA model, according to the usual criterion of reliability in QSAR studies (q2 ≥ 0.5 and r2 ≥ 0.9) (Fang et al., 2011; Golbraikh and Tropsha 2002; Tan et al., 2017; Zheng et al., 2017)....

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Journal ArticleDOI
TL;DR: In this article , the authors developed a systematic molecular design, screening, and performance evaluation method to design functionally improved, environmentally friendly and synthesizable aromatic amine alternatives for the first time.
Journal ArticleDOI
TL;DR: In this paper , the results of computational modeling studies on PDE inhibitors as anti-Alzheimer agents are discussed, and the authors discuss the effect of hydrogen bonds, π-π stacking, and volume on the interaction of the molecules with the catalytic site of PDEs.
Abstract: Neurodegenerative diseases are pathological disorders inducing a gradual loss of neuronal functionality presenting a multifactorial character. Among them, Alzheimer’s disease (AD) causes the most well-known type of dementia and one of the major representatives. Due to the multifactorial etiology of AD, pleiotropic treatments are getting increasing importance. Phosphodiesterases (PDEs) are treated as molecular targets for many pathological situations. Neurodegenerative manifestations are among them. Regulation of the concentration of cAMP and/or cGMP is related to the inhibition of PDEs located in the human brain. In this chapter, we will discuss the results of computational modeling studies on PDE inhibitors as anti-Alzheimer agents. Hydrogen bonds, π–π stacking, and volume are important for the interaction of the molecules with the catalytic site of PDEs.