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题名: Exploring the structure determinants of pyrazinone derivatives as PDE5 3HC8 inhibitors: An in silico analysis
作者: Li, Yan1;  Wu, Wenzhao1;  Ren, Hong2, 3;  Wang, Jinghui1;  Zhang, Shuwei1;  Li, Guohui3;  Yang, Ling4
关键词: PDE5 ;  Pyrazinone-based inhibitors ;  3D-QSAR ;  Molecular docking ;  Molecular dynamics
刊名: JOURNAL OF MOLECULAR GRAPHICS & MODELLING
发表日期: 2012-09-01
DOI: 10.1016/j.jmgm.2012.07.003
卷: 38, 页:112-122
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine ;  Technology ;  Physical Sciences
类目[WOS]: Biochemical Research Methods ;  Biochemistry & Molecular Biology ;  Computer Science, Interdisciplinary Applications ;  Crystallography ;  Mathematical & Computational Biology
研究领域[WOS]: Biochemistry & Molecular Biology ;  Computer Science ;  Crystallography ;  Mathematical & Computational Biology
英文摘要: Phosphodiesterase type 5 (PDE5) inhibitors are clinically indicated for the treatment of erectile dysfunction, pulmonary hypertension and various other diseases. In this work, both ligand- and receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 122 pyrazinone derivatives as PDE inhibitors. The resultant optimum 3D-QSAR model exhibits a proper predictive ability as indicated by the statistical results of Q(2) of 0.584, R-ncv(2) of 0.884 and R-pre(2) of 0.817, respectively. In addition, docking analysis and molecular dynamics (MD) simulation were also applied to elucidate the probable binding modes of these inhibitors. Our main findings are: (1) Introduction of bulky, electropositive and hydrophobic substituents at 12- and 19-positions can increase the biological activities. (2) N atom at 8-position is detrimental to the inhibitor activity, and the effect of N atoms at 5- and 6-positions on compound activity is co-determined by both the hydrophobic force and the pi-pi stacking interaction. (3) Bulky and hydrophilic substitutions are favored at the 27-position of ring D. (4) Electronegative and hydrophilic substitutions around 5- and 6-positions increase the inhibitory activity. (5) Hydrophobic forces and pi-pi stacking interaction with Phe786 and Phe820 are crucial in determining the binding of pyrazinone derivatives to PDE5. (6) Bulky substitutions around ring C favors selectivity against PDE11, while bulky groups near the 21-position disfavor the selectivity. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate future rational designs of novel PDE5 inhibitors with improved activity and selectivity. (C) 2012 Elsevier Inc. All rights reserved.
关键词[WOS]: MOLECULAR SIMILARITY INDEXES ;  FIELD ANALYSIS COMFA ;  ERECTILE DYSFUNCTION ;  PHOSPHODIESTERASE-5 INHIBITORS ;  DRUG DESIGN ;  BIOLOGICAL EVALUATION ;  CROSS-VALIDATION ;  COMBINED 3D-QSAR ;  ANALYSIS COMSIA ;  P-GLYCOPROTEIN
语种: 英语
WOS记录号: WOS:000313392800012
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/143108
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Dalian Univ Technol, Dept Mat Sci & Chem Engn, Dalian 116023, Liaoning, Peoples R China
2.Shandong Univ, Sch Med, Qi Lu Hosp, Dept Ophthalmol, Jinan 250012, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Mol Modeling & Design, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
4.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Grad Sch, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Li, Yan,Wu, Wenzhao,Ren, Hong,et al. Exploring the structure determinants of pyrazinone derivatives as PDE5 3HC8 inhibitors: An in silico analysis[J]. JOURNAL OF MOLECULAR GRAPHICS & MODELLING,2012,38:112-122.
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