Exploring binding mechanisms of VEGFR2 with three drugs lenvatinib, sorafenib, and sunitinib by molecular dynamics simulation and free energy calculation

doi:10.1111/cbdd.13493

	Exploring binding mechanisms of VEGFR2 with three drugs lenvatinib, sorafenib, and sunitinib by molecular dynamics simulation and free energy calculation
	Wang, Yu 2,3; Peng, Cheng 3; Wang, Guimin 3; Xu, Zhijian 3; Luo, Yongfeng 2; Wang, Jinan 1,3,4; Zhu, Weiliang 3
刊名	CHEMICAL BIOLOGY & DRUG DESIGN
	2019-05-01
卷号	93 期号:5 页码:934-948
关键词	hydrophobic contact scanning MM GBSA molecular dynamics simulation VEGFR2-drugs interaction
ISSN号	1747-0277
DOI	10.1111/cbdd.13493
通讯作者	Luo, Yongfeng(yfluo@csuft.edu.cn) ; Wang, Jinan(jawang1985@gmail.com)
英文摘要	Lenvatinib (LEN), sorafenib (SOR), and sunitinib (SUN) are drugs targeting vascular endothelial growth factor receptor 2 (VEGFR2). Despite sharing similar chemical structures and bioactivities, LEN and SOR bind to different functional states of VEGFR2, viz. DFG-in and DFG-out state, respectively. SUN binds to the DFG-out state of VEGFR2 just like SOR but with less potency. Thus, detail binding mechanisms between VEGFR2 and these drugs, especially dynamic interaction, are valuable for future drug design. In the present work, molecular dynamics simulation, essential dynamic analysis, and molecular mechanics/generalized born surface area were performed to these VEGFR2-drugs systems. Rank of calculated binding affinities is in accordance with the experimental data. The binding free energy calculation suggests that van der Waals interaction plays a vital role in the binding. Per-residue free energy decomposition indicates that residues L840, V848, A866, E885, L889, V899, V916, F918, C919, L1035, C1045, D1046, and F1047 play an important role in the binding between VEGFR2 and LEN/SOR. While residues L840, V848, E917, F918, C919, G922, L1035, and F1047 contribute the major hydrophobic interaction for SUN binding to the receptor. Our results also reveal that residue E885/D1046 plays a vital role in binding via forming hydrogen bonds with drugs.
资助项目	National Natural Science Foundation of China[81573350] ; National Natural Science Foundation of China[21403283] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund[U1501501] ; National Key Research and Development Program of China[2017YFB0202600] ; National Key Research and Development Program of China[2016YFA0502301]
WOS关键词	ENDOTHELIAL GROWTH-FACTOR ; RENAL-CELL CARCINOMA ; PARTICLE MESH EWALD ; KINASE INHIBITORS ; CONFORMATIONAL-CHANGES ; DOCKING ; ANGIOGENESIS ; PERFORMANCE ; DISCOVERY ; MM/GBSA
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种	英语
出版者	WILEY
WOS记录号	WOS:000468814500022
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289814]
专题	中国科学院上海药物研究所
通讯作者	Luo, Yongfeng; Wang, Jinan
作者单位	1.Univ Kansas, Ctr Computat Biol, Lawrence, KS 66045 USA 2.Cent South Univ Forestry & Technol, Coll Sci, Hunan Prov Key Lab Mat Surface & Interface Sci &, Changsha, Hunan, Peoples R China 3.Chinese Acad Sci, CAS Key Lab Receptor Res, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai, Peoples R China 4.Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA
推荐引用方式 GB/T 7714	Wang, Yu,Peng, Cheng,Wang, Guimin,et al. Exploring binding mechanisms of VEGFR2 with three drugs lenvatinib, sorafenib, and sunitinib by molecular dynamics simulation and free energy calculation[J]. CHEMICAL BIOLOGY & DRUG DESIGN,2019,93(5):934-948.
APA	Wang, Yu.,Peng, Cheng.,Wang, Guimin.,Xu, Zhijian.,Luo, Yongfeng.,...&Zhu, Weiliang.(2019).Exploring binding mechanisms of VEGFR2 with three drugs lenvatinib, sorafenib, and sunitinib by molecular dynamics simulation and free energy calculation.CHEMICAL BIOLOGY & DRUG DESIGN,93(5),934-948.
MLA	Wang, Yu,et al."Exploring binding mechanisms of VEGFR2 with three drugs lenvatinib, sorafenib, and sunitinib by molecular dynamics simulation and free energy calculation".CHEMICAL BIOLOGY & DRUG DESIGN 93.5(2019):934-948.