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	Studies of the mechanism of selectivity of protein tyrosine phosphatase 113 (ptp1b) bidentate inhibitors using molecular dynamics simulations and free energy calculations
	Fang, Lei1; Zhang, Huai2; Cui, Wei1; Ji, Mingjun1
刊名	Journal of chemical information and modeling
	2008-10-01
卷号	48期号:10页码:2030-2041
ISSN号	1549-9596
DOI	10.1021/ci800104s
通讯作者	Ji, mingjun(jmj@gucas.ac.cn)
英文摘要	Bidentate inhibitors of protein tyrosine phosphatase 1b (ptp1b) are considered as a group of ideal inhibitors with high binding potential and high selectivity in treating type ii diabetes. in this paper, the binding models of five bidentate inhibitors to ptp1b, tcptp, and shp-2 were investigated and compared by using molecular dynamics (md) simulations and free energy calculations. the binding free energies were computed using the molecular mechanics/poisson-boltzmann surface area (mm/pbsa) methodology. the calculation results show that the predicted free energies of the complexes are well consistent with the experimental data. the molecular mechanics/generalized born surface area (mm/gbsa) free energy decomposition analysis indicates that the residues arg24, arg254, and gln262 in the second binding site of ptp 1b are essential for the high selectivity of inhibitors. furthermore, the residue phe182 close to the active site is also important for the selectivity and the binding affinity of the inhibitors. according to our analysis, it can be concluded that in most cases the polarity of the portion of the inhibitor that binds to the second binding site of the protein is positive to the affinity of the inhibitors while negative to the selectivity of the inhibitors. we expect that the information we obtained here can help to develop potential ptp1b inhibitors with more promising specificity.
WOS关键词	INSULIN SIGNAL-TRANSDUCTION ; AMPHIPHYSIN-1 SH3 DOMAIN ; CRYSTAL-STRUCTURE ; DRUG-RESISTANCE ; 1B INHIBITOR ; BINDING-SITE ; FORCE-FIELD ; MICE ; SENSITIVITY ; PREDICTION
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
WOS类目	Chemistry, Medicinal ; Chemistry, Multidisciplinary ; Computer Science, Information Systems ; Computer Science, Interdisciplinary Applications
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000260428800012
内容类型	期刊论文
URI标识	http://www.corc.org.cn/handle/1471x/2385112
专题	中国科学院大学
通讯作者	Ji, Mingjun
作者单位	1.Chinese Acad Sci, Grad Univ, Coll Chem & Chem Engn, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Grad Univ, Lab Computat Geodynam, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Fang, Lei,Zhang, Huai,Cui, Wei,et al. Studies of the mechanism of selectivity of protein tyrosine phosphatase 113 (ptp1b) bidentate inhibitors using molecular dynamics simulations and free energy calculations[J]. Journal of chemical information and modeling,2008,48(10):2030-2041.
APA	Fang, Lei,Zhang, Huai,Cui, Wei,&Ji, Mingjun.(2008).Studies of the mechanism of selectivity of protein tyrosine phosphatase 113 (ptp1b) bidentate inhibitors using molecular dynamics simulations and free energy calculations.Journal of chemical information and modeling,48(10),2030-2041.
MLA	Fang, Lei,et al."Studies of the mechanism of selectivity of protein tyrosine phosphatase 113 (ptp1b) bidentate inhibitors using molecular dynamics simulations and free energy calculations".Journal of chemical information and modeling 48.10(2008):2030-2041.

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