Molecular Dynamics Simulation of the Selectivity of Fedratinib Complex with JAK2/JAK3†

doi:10.7503/cjcu20170657

Abstract

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

CLC Number:

O641

TrendMD:

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^†[J]. Chem. J. Chinese Universities, 2018, 39(7): 1540.

Figures/Tables 11

References 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