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题名: Profiling the Structural Determinants of Heteroarylnitrile Scaffold-Based Derivatives as Falcipain-2 Inhibitors by In Silico Methods
作者: Wang, Jinghui1;  Li, Yan1;  Yang, Yinfeng1;  Zhang, Shuwei1;  Yang, Ling2
关键词: falcipain-2 ;  3D-QSAR ;  molecular docking ;  molecular dynamics
刊名: CURRENT MEDICINAL CHEMISTRY
发表日期: 2013-05-01
卷: 20, 期:15, 页:2032-2042
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 ;  Chemistry, Medicinal ;  Pharmacology & Pharmacy
研究领域[WOS]: Biochemistry & Molecular Biology ;  Pharmacology & Pharmacy
英文摘要: Evidence indicates that cysteine protease falcipain-2 plays essential role in malaria parasites; therefore the potent and selective inhibitors of falcipain-2 may be therapeutically useful drugs for treatment of various forms of malaria parasite plasmodium. In order to understand the structure-activity correlation of falcipain-2 inhibitors, a set of ligand- and receptor-based 3D-QSAR models were, for the first time, developed in the present work employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) for 240 promising molecules. Based on the ligand- based alignment, an optimal 3D-QSAR model was obtained with good predictive power of Q(2) - 0.501, R-ncv(2) - 0.890, SEE - 0.282, F - 153.522 and R-pred(2) - 0.768. And the contour maps intuitively suggest where to modify the molecular structures in order to improve the binding affinity. In addition, docking analysis and molecular dynamics simulation (MD) study were also carried out on the dataset with purpose of exploring the detailed binding modes of ligand in the falcipain-2 binding pocket. The combination of docking analysis and MD simulation shows that Gly83, Trp43 and Ala175 which formed several H-bonds are crucial for falcipain-2 inhibitors. The analysis of the best QSAR model reveals the structural features related to the activity, and provides an insight into molecular mechanisms of inhibition and possible modification of the molecules for better activity.
关键词[WOS]: CYSTEINE PROTEASE INHIBITORS ;  MOLECULAR-DYNAMICS ;  DIHYDROFOLATE-REDUCTASE ;  KINASE INHIBITORS ;  COMBINED 3D-QSAR ;  NEURAL-NETWORKS ;  QSAR MODELS ;  MALARIA ;  DOCKING ;  SELECTION
语种: 英语
WOS记录号: WOS:000317661800008
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/137979
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.Chinese Acad Sci, Grad Sch, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Wang, Jinghui,Li, Yan,Yang, Yinfeng,et al. Profiling the Structural Determinants of Heteroarylnitrile Scaffold-Based Derivatives as Falcipain-2 Inhibitors by In Silico Methods[J]. CURRENT MEDICINAL CHEMISTRY,2013,20(15):2032-2042.
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