DICP OpenIR
Inhibition mechanism exploration of quinoline derivatives as PDE10A inhibitors by in silico analysis
Wu, Qian1; Gao, Qingping2; Guo, Huanmei1; Li, Dan1; Wang, Jinghui3; Gao, Weimin3; Han, Chunxiao3; Li, Yan3; Yang, Ling4
Source PublicationMOLECULAR BIOSYSTEMS
2013
DOI10.1039/c2mb25501d
Volume9Issue:3Pages:386-397
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectBiochemistry & Molecular Biology
WOS Research AreaBiochemistry & Molecular Biology
WOS KeywordPHOSPHODIESTERASE 10A INHIBITORS ; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES ; STRIATUM-ENRICHED PHOSPHODIESTERASE ; ORALLY-ACTIVE PYRAZOLOQUINOLINES ; MOLECULAR SIMILARITY INDEXES ; IMMUNOHISTOCHEMICAL LOCALIZATION ; SUBSTRATE-SPECIFICITY ; DRUG DEVELOPMENT ; FIELD ANALYSIS ; SCHIZOPHRENIA
AbstractAs 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.
Language英语
WOS IDWOS:000314473500007
Citation statistics
Cited Times:6[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/137813
Collection中国科学院大连化学物理研究所
Affiliation1.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
GB/T 7714
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.
APA Wu, Qian.,Gao, Qingping.,Guo, Huanmei.,Li, Dan.,Wang, Jinghui.,...&Yang, Ling.(2013).Inhibition mechanism exploration of quinoline derivatives as PDE10A inhibitors by in silico analysis.MOLECULAR BIOSYSTEMS,9(3),386-397.
MLA Wu, Qian,et al."Inhibition mechanism exploration of quinoline derivatives as PDE10A inhibitors by in silico analysis".MOLECULAR BIOSYSTEMS 9.3(2013):386-397.
Files in This Item:
There are no files associated with this item.
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Wu, Qian]'s Articles
[Gao, Qingping]'s Articles
[Guo, Huanmei]'s Articles
Baidu academic
Similar articles in Baidu academic
[Wu, Qian]'s Articles
[Gao, Qingping]'s Articles
[Guo, Huanmei]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Wu, Qian]'s Articles
[Gao, Qingping]'s Articles
[Guo, Huanmei]'s Articles
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.