分子动力学模拟研究Fedratinib-JAK2/JAK3选择性

doi:10.7503/cjcu20170657

摘要/Abstract

摘要：

通过动力学模拟获得JAK2高选择性抑制剂Fedratinib在JAK2和JAK3激酶中的结合构象, 结合自由能的计算结果表明Fedratinib在JAK2中更稳定. 将能量分解到结合位点氨基酸, 分析发现当分子在JAK2中占据P-loop区的疏水口袋, 并与附近Arg980和Asp994等氨基酸形成氢键时, 可以增加相对于JAK2的选择性.

关键词: JAK2抑制剂, 选择性, 分子动力学, 自由结合能

Abstract:

Molecular dynamic(MD) simulation was carried out in both JAK2-Fedratinib and JAK3-Fedratinib complex, respectively. Binding free energy was calculated in utilize the trajectory of MD. The results indicated the energy of JAK2-Fedratinib was lower than that of JAK3-Fedratinib, which demonstrate the different enzyme activity in two kinase. When binding free energy was decomposed into each residue of binding site, it could be found that when molecule occupies the pockets below P-loop and form H-bonds with residues nearby the selectivity for JAK2 over JAK3 may be highlighted. The results can provide insights for further development of more potent and selective JAK2 inhibitors.

Key words: JAK2 inhibitor, Selectivity, Molecular dynamic, Binding free energy

中图分类号:

O641

TrendMD:

刘海春, 卢帅, 张艳敏, 周伟能, 尹凌枫, 朱露, 赵珺楠, 陆涛, 陈亚东. 分子动力学模拟研究Fedratinib-JAK2/JAK3选择性. 高等学校化学学报, 2018, 39(7): 1540.

LIU Haichun, LU Shuai, ZHANG Yanmin, ZHOU Weineng, YIN Lingfeng, ZHU Lu, ZHAO Junnan, LU Tao, CHEN Yadong. Molecular Dynamics Simulation of the Selectivity of Fedratinib Complex with JAK2/JAK3^†. Chem. J. Chinese Universities, 2018, 39(7): 1540.

图/表 11

参考文献 29

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Enzyme	Acceptor	Donor	Distance/nm	Angle/(°)	Occupied(%)
JAK2	Fed@O3	980@NH2: HH21	0.292(±0.014)	18.58(±9.75)	99.34
	Fed@N2	932@N: H	0.311(±0.014)	18.14(±9.65)	98.34
	932@O	Fed@N3: H2	0.302(±0.016)	30.67(±11.75)	96.26
	Fed@O2	980@NE: HE	0.311(±0.019)	35.50(±13.31)	71.75
	994@OD1	Fed@N6: HH27	0.305(±0.019)	21.96(±12.61)	50.37
	Fed@O2	980@NH2: HH21	0.329(±0.016)	47.30(±8.60)	23.14
	994@OD2	Fed@N6: H27	0.308(±0.020)	20.68(±11.45)	22.30
	Fed@O3	980@NE: HE	0.333(±0.014)	43.87(±7.05)	19.98
JAK3	Fed@N2	905@N: H	0.314(±0.014)	17.23(±9.48)	97.42
	905@O	Fed@N3: H3	0.301(±0.016)	34.29(±12.68)	92.76
	Fed@O3	830@N: H	0.315(±0.019)	50.26(±8.20)	5.42
	Fed@O2	855@NZ: HZ1	0.328(±0.014)	43.66(±6.41)	0.10

Enzyme	Acceptor	Donor	Distance/nm	Angle/(°)	Occupied(%)
JAK2	Fed@O3	980@NH2: HH21	0.292(±0.014)	18.58(±9.75)	99.34
	Fed@N2	932@N: H	0.311(±0.014)	18.14(±9.65)	98.34
	932@O	Fed@N3: H2	0.302(±0.016)	30.67(±11.75)	96.26
	Fed@O2	980@NE: HE	0.311(±0.019)	35.50(±13.31)	71.75
	994@OD1	Fed@N6: HH27	0.305(±0.019)	21.96(±12.61)	50.37
	Fed@O2	980@NH2: HH21	0.329(±0.016)	47.30(±8.60)	23.14
	994@OD2	Fed@N6: H27	0.308(±0.020)	20.68(±11.45)	22.30
	Fed@O3	980@NE: HE	0.333(±0.014)	43.87(±7.05)	19.98
JAK3	Fed@N2	905@N: H	0.314(±0.014)	17.23(±9.48)	97.42
	905@O	Fed@N3: H3	0.301(±0.016)	34.29(±12.68)	92.76
	Fed@O3	830@N: H	0.315(±0.019)	50.26(±8.20)	5.42
	Fed@O2	855@NZ: HZ1	0.328(±0.014)	43.66(±6.41)	0.10

Contribution	JAK2		JAK3
Contribution	Mean/(kJ·mol^-1)	Std./(kJ·mol^-1)	Mean/(kJ·mol^-1)	Std./(kJ·mol^-1)
ΔE_ele/(kJ·mol^-1)	-130.79	5.14	-87.99	3.23
ΔE_vdw/(kJ·mol^-1)	-254.09	3.26	-237.19	3.35
ΔE_intra/(kJ·mol^-1)	0	0	0	0
ΔE_gas/(kJ·mol^-1)	-384.89	5.80	-325.18	4.31
ΔG_np/(kJ·mol^-1)	-32.09	0.23	-32.13	0.60
ΔG_pb/(kJ·mol^-1)	221.67	4.35	206.35	4.21
ΔG_pbele/(kJ·mol^-1)	90.88	4.57	118.41	4.22
ΔG_pb,tot/(kJ·mol^-1)	-195.31	5.04	-150.92	4.63
ΔG_gb/(kJ·mol^-1)	180.96	2.85	168.74	2.82
ΔG_gbele/(kJ·mol^-1)	50.17	3.39	80.75	2.30
ΔG_gb,tot/(kJ·mol^-1)	-236.02	4.23	-188.53	3.26

Contribution	JAK2		JAK3
Contribution	Mean/(kJ·mol^-1)	Std./(kJ·mol^-1)	Mean/(kJ·mol^-1)	Std./(kJ·mol^-1)
ΔE_ele/(kJ·mol^-1)	-130.79	5.14	-87.99	3.23
ΔE_vdw/(kJ·mol^-1)	-254.09	3.26	-237.19	3.35
ΔE_intra/(kJ·mol^-1)	0	0	0	0
ΔE_gas/(kJ·mol^-1)	-384.89	5.80	-325.18	4.31
ΔG_np/(kJ·mol^-1)	-32.09	0.23	-32.13	0.60
ΔG_pb/(kJ·mol^-1)	221.67	4.35	206.35	4.21
ΔG_pbele/(kJ·mol^-1)	90.88	4.57	118.41	4.22
ΔG_pb,tot/(kJ·mol^-1)	-195.31	5.04	-150.92	4.63
ΔG_gb/(kJ·mol^-1)	180.96	2.85	168.74	2.82
ΔG_gbele/(kJ·mol^-1)	50.17	3.39	80.75	2.30
ΔG_gb,tot/(kJ·mol^-1)	-236.02	4.23	-188.53	3.26

Residue		ΔE_vdw/(kJ·mol^-1)		ΔE_ele/(kJ·mol^-1)		ΔE_gas/(kJ·mol^-1)		ΔG_gb,tot/(kJ·mol^-1)
JAK2	JAK3	JAK2	JAK3	JAK2	JAK3	JAK2	JAK3	JAK2	JAK3
Met929	Met902	-2.80	-2.30	1.42	0.59	-1.38	-1.76	-2.01	-1.88
Val911	Val884	-2.09	-1.46	0.67	0.67	-1.42	-0.79	-1.84	-1.34