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题名: Inhibition mechanism exploration of quinoline derivatives as PDE10A inhibitors by in silico analysis
作者: Wu, Qian1;  Gao, Qingping2;  Guo, Huanmei1;  Li, Dan1;  Wang, Jinghui3;  Gao, Weimin3;  Han, Chunxiao3;  Li, Yan3;  Yang, Ling4
刊名: MOLECULAR BIOSYSTEMS
发表日期: 2013
DOI: 10.1039/c2mb25501d
卷: 9, 期:3, 页:386-397
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Biochemistry & Molecular Biology
研究领域[WOS]: Biochemistry & Molecular Biology
英文摘要: As a potential target for the treatment of schizophrenia, the dual cAMP/cGMP hydrolyzing enzyme PDE10A has attracted a significant amount of attention. In the present work, the inhibition mechanism of 116 structurally diverse quinoline derivatives as PDE10A inhibitors was explored by 3D-QSAR, molecular docking and molecular dynamics (MD) simulations. The QSAR models based on the training set containing 88 molecules were established by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The resultant optimum CoMSIA model showed strong predictability with a Q(2) of 0.497, an R-ncv(2) of 0.964 and an R-pre(2) of 0.885. Furthermore, there was good consistency between the CoMSIA model, docking and MD results. Our findings are: (1) bulky substituents at the 8-position and ring D increase the biological activity. (2) The areas around the 14-position and ring D are the electrostatic and hydrophobic sensitive regions. (3) H-bonds, pi-pi stacking interactions and hydrophobic contacts are crucial in determining the binding affinity to PDE10A. (4) The six-membered heterocyclic group at ring D, especially a heterobenzene ring, containing the atom as an H-bond acceptor at the 18-position is essential to water-mediated H-bond networks and favorable in enhancing the inhibitory potency. These models and the derived information may help to provide better understanding of the interaction mechanism of PDE10A inhibitors and to facilitate lead optimization and novel inhibitors' design.
关键词[WOS]: PHOSPHODIESTERASE 10A INHIBITORS ;  CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES ;  STRIATUM-ENRICHED PHOSPHODIESTERASE ;  ORALLY-ACTIVE PYRAZOLOQUINOLINES ;  MOLECULAR SIMILARITY INDEXES ;  IMMUNOHISTOCHEMICAL LOCALIZATION ;  SUBSTRATE-SPECIFICITY ;  DRUG DEVELOPMENT ;  FIELD ANALYSIS ;  SCHIZOPHRENIA
语种: 英语
WOS记录号: WOS:000314473500007
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/137813
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.Weifang Univ, Microscale Sci Inst, Weifang 261061, Shandong, Peoples R China
2.Weifang Vocat Coll, Sch Chem Engn, Weifang 261031, Peoples R China
3.Dalian Univ Technol, Dept Mat Sci & Chem Engn, Dalian 116024, Liaoning, Peoples R China
4.Chinese Acad Sci, Dalian Inst Chem Phys, Grad Sch, Lab Pharmaceut Resource Discovery, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Wu, Qian,Gao, Qingping,Guo, Huanmei,et al. Inhibition mechanism exploration of quinoline derivatives as PDE10A inhibitors by in silico analysis[J]. MOLECULAR BIOSYSTEMS,2013,9(3):386-397.
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