Computational insights into different inhibition modes of the kappa-opioid receptor with antagonists LY2456302 and JDTic

doi:10.1039/c5ra24911b

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	Computational insights into different inhibition modes of the kappa-opioid receptor with antagonists LY2456302 and JDTic
	Cheng, Jianxin 1,2; Li, Weihua 2; Liu, Guixia 2; Zhu, Weiliang1 ; Tang, Yun 2
刊名	RSC ADVANCES
	2016
卷号	6 期号:17 页码:13626-13635
ISSN号	2046-2069
DOI	10.1039/c5ra24911b
文献子类	Article
英文摘要	In drug design and discovery, ligand binding kinetics combines pharmacokinetics and pharmacodynamics and more and more attention is paid to it. The kappa-opioid G-protein coupled receptor (kappa-OR) has been determined to be a promising drug target for the treatment of depression-and anxiety-related diseases. Among the kappa-OR selective antagonists, JDTic is a failed antidepressant with a short drug-target residence time (RT), whereas LY2456302 exhibits better effects with a longer RT than JDTic. To investigate the inhibition mechanism of the kappa-OR induced by the two ligands, unbiased molecular dynamics and well-tempered metadynamics simulations were performed on JDTic-kappa-OR and LY2456302-kappa-OR complexes. Through detailed analyses of the simulations, a strong but single interaction mode was found to be responsible for the adverse effects and short RT of JDTic, which could be considered as an alert for other chemotypes, whereas LY2456302 was more advanced, mainly due to its multiple metastable states. Based on Eyring's equation, the relative RT of LY2456302/JDTic, determined from the activation free energy of dissociation Delta G(off)(not equal), was efficiently calculated and was in good agreement with experimental data. Thus, these simulations might be helpful for the further design of antidepressants targeting kappa-OR with reasonable RT.
资助项目	National Natural Science Foundation of China[81273438]
WOS关键词	PROTEIN-COUPLED RECEPTORS ; FREE-ENERGY LANDSCAPE ; GENERAL FORCE-FIELD ; ACCELERATED MOLECULAR-DYNAMICS ; TARGET RESIDENCE TIME ; BINDING-KINETICS ; ACCURATE DOCKING ; SIMULATION ; DISCOVERY ; MECHANISM
WOS研究方向	Chemistry
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000369639400005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276252]
专题	药物发现与设计中心
通讯作者	Tang, Yun
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Meilong Rd, Shanghai 200237, Peoples R China;
推荐引用方式 GB/T 7714	Cheng, Jianxin,Li, Weihua,Liu, Guixia,et al. Computational insights into different inhibition modes of the kappa-opioid receptor with antagonists LY2456302 and JDTic[J]. RSC ADVANCES,2016,6(17):13626-13635.
APA	Cheng, Jianxin,Li, Weihua,Liu, Guixia,Zhu, Weiliang,&Tang, Yun.(2016).Computational insights into different inhibition modes of the kappa-opioid receptor with antagonists LY2456302 and JDTic.RSC ADVANCES,6(17),13626-13635.
MLA	Cheng, Jianxin,et al."Computational insights into different inhibition modes of the kappa-opioid receptor with antagonists LY2456302 and JDTic".RSC ADVANCES 6.17(2016):13626-13635.