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学科主题: 物理化学
题名: Identification of Novel Potential beta-N-Acetyl-D-Hexosaminidase Inhibitors by Virtual Screening, Molecular Dynamics Simulation and MM-PBSA Calculations
作者: Liu, Jianling2;  Liu, Mengmeng1, 2;  Yao, Yao1;  Wang, Jinan1;  Li, Yan3;  Li, Guohui4;  Wang, Yonghua1, 5, 6
通讯作者: WangYonghua
关键词: beta-N-acetyl-D-hexosaminidase ;  OfHex1 ;  inhibitor ;  virtual screening ;  molecular dynamics ;  MM/PBSA
刊名: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
发表日期: 2012-04-01
DOI: 10.3390/ijms13044545
卷: 13, 期:4, 页:4545-4563
收录类别: SCI
文章类型: Article
部门归属: 11
项目归属: 1106
产权排名: 4,6
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
英文摘要: Chitinolytic beta-N-acetyl-D-hexosaminidases, as a class of chitin hydrolysis enzyme in insects, are a potential species-specific target for developing environmentally-friendly pesticides. Until now, pesticides targeting chitinolytic beta-N-acetyl-D-hexosaminidase have not been developed. This study demonstrates a combination of different theoretical methods for investigating the key structural features of this enzyme responsible for pesticide inhibition, thus allowing for the discovery of novel small molecule inhibitors. Firstly, based on the currently reported crystal structure of this protein (OfHex1.pdb), we conducted a pre-screening of a drug-like compound database with 8 x 10(6) compounds by using the expanded pesticide-likeness criteria, followed by docking-based screening, obtaining 5 top-ranked compounds with favorable docking conformation into OfHex1. Secondly, molecular docking and molecular dynamics simulations are performed for the five complexes and demonstrate that one main hydrophobic pocket formed by residues Trp424, Trp448 and Trp524, which is significant for stabilization of the ligand-receptor complex, and key residues Asp477 and Trp490, are respectively responsible for forming hydrogen-bonding and pi-pi stacking interactions with the ligands. Finally, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis indicates that van der Waals interactions are the main driving force for the inhibitor binding that agrees with the fact that the binding pocket of OfHex1 is mainly composed of hydrophobic residues. These results suggest that screening the ZINC database can maximize the identification of potential OfHex1 inhibitors and the computational protocol will be valuable for screening potential inhibitors of the binding mode, which is useful for the future rational design of novel, potent OfHex1-specific pesticides.
关键词[WOS]: AMBER FORCE-FIELD ;  CHITINASE INHIBITOR ;  AUTOMATED DOCKING ;  BINDING ;  DEGRADATION ;  DERIVATIVES ;  AFFINITIES ;  MECHANICS ;  LIGANDS ;  ARGIFIN
语种: 英语
WOS记录号: WOS:000303454700035
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/118178
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.NW A&F Univ, Ctr Bioinformat, Yangling 712100, Shaanxi, Peoples R China
2.NW Univ Xian, Coll Life Sci, Xian 710069, Shaanxi, Peoples R China
3.Dalian Univ Technol, Sch Chem Engn, Dalian 116012, Peoples R China
4.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian 116023, Peoples R China
5.NW A&F Univ, Coll Plant Protect, Yangling 712100, Peoples R China
6.NW A&F Univ, State Key Lab Crop Stress Biol Arid Areas, Yangling 712100, Peoples R China

Recommended Citation:
Liu, Jianling,Liu, Mengmeng,Yao, Yao,et al. Identification of Novel Potential beta-N-Acetyl-D-Hexosaminidase Inhibitors by Virtual Screening, Molecular Dynamics Simulation and MM-PBSA Calculations[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2012,13(4):4545-4563.
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