Computational insight into dengue virus NS2B-NS3 protease inhibition: A combined ligand- and structure-based approach

被引:17
|
作者
Chen, Junning [1 ]
Jiang, Hailun [1 ]
Li, Fangfei [1 ]
Hu, Baichun [1 ]
Wang, Ying [1 ]
Wang, MingXing [1 ]
Wang, Jian [1 ]
Cheng, Maosheng [1 ]
机构
[1] Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drugs Design & Discovery, Shenyang 110016, Liaoning, Peoples R China
基金
中国国家自然科学基金;
关键词
Dengue; NS2B-NS3; protease; Molecular docking; Pharmacophore models; MEDICINAL CHEMISTRY; DISCOVERY; IDENTIFICATION; TARGET;
D O I
10.1016/j.compbiolchem.2018.09.010
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
The NS2B-NS3 protease is essential for the replication process of Dengue Virus, which make it an attractive target for anti-virus drugs. Since a considerable number of NS2B-NS3 protease inhibitors have been reported so far, it is significant for the discovery of more effective antivirus compounds with the essential structure-activity relationship extracted from known inhibitors. In this perspective, the relationship between the chemical features of inhibitors and their biological activities was investigated with a combined ligand- and structure-based approach. Furthermore, 3D pharmacophore models were generated with the best selected, which consisted of five chemical features: one ring aromatic group, one hydrophobic group, one hydrogen bond donor and two hydrogen bond acceptors (RHDAA). Subsequently, molecular docking was employed to explore the specific allosteric site for non-peptidic inhibitors to bind, which was proved to be located behind the catalytic triad. Taken the results of both molecular docking and pharmacophore modeling into consideration, a model of receptor-ligand interaction was obtained with four essential chemical features including aromatic rings and hydrogen bonds. This research provided an accurate binding model for the discovery and optimization of NS2B-NS3 protease inhibitors.
引用
收藏
页码:261 / 271
页数:11
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