Molecular Modification of Polychlorinated Biphenyl Dihydroxy Derivatives Through Molecular Docking Associated with CoMSIA/HQSAR Models†

doi:10.7503/cjcu20170402

Abstract

Abstract:

Molecular docking of dihydroxy polychlorinated biphenyls, which are atmospheric degradation products of dioxin-like polychlorinated biphenyls(PCBs), with dihydroxybiphenyl dioxygenase(Bphc, PDB ID: 1KW6) was studied, and the comparative molecular similarity indices analysis(CoMSIA) and the hologram quantitative structure-activity relationship(HQSAR) model were constructed, in which the molecular structure parameters as independent variables and total score(K_d, representing the docking activity) as the dependent variable, meanwhile, molecular modification of dihydroxy polychlorinated biphenyls was carried out. The results showed that Bphc enzymes can degrade all kinds of dihydroxy polychlorinated biphenyls in different degrees; the amino acid residues(His145, Val147, Ile174, His194, His208, His209, His240, Asn242, Tyr249, Thr280) affect the docking activity of Bphc enzyme, and also, more the hydrogen bond formed by the docking of dihydroxy polychlorinated biphenyls with amino acid residues, the higher the docking activity. A method for accurate determination of molecular substitution activity of dihydroxy polychlorinated biphenyls coupled with CoMSIA and HQSAR model was established. Based on the above, the 5,6-2OH-CB60 was as the target molecule, and eight novel molecules with improved scoring function were designed, whose docking activity increased 65%—185%, toxicity(IC₅₀) decreased 10%—83%, bioaccumulation(BCF) decreased 4%—27%, migration(K_OA) and half-life(t_1/2) remained unchanged. The synthesis of the reaction pathways of novel molecules could confirm that the dihydroxy polychlorinated biphenyls 5,6-2OH-CB60 can react with active radicals and active molecules to form novel 5,6-2OH-CB60 molecules, which means the dioxin-like polychlorinated biphenyls can be degraded by atmospheric oxidation to produce a new type of two dihydroxy polychlorinated biphenyl whose enzyme degradation is remarkably improved, so as to further control the environmental behavior of dioxin-like PCBs.

Key words: Dioxin-like polychlorinated biphenyl(PCB), Dihydroxy polychlorinated biphenyl, Bphc, Molecular docking, Comparative molecular similarity indices analysis(CoMSIA), Hologram quantitative structureactivity relationship(HQSAR)

CLC Number:

O641
O631

TrendMD:

XIN Meiling, CHU Zhenhua, LI Yu. Molecular Modification of Polychlorinated Biphenyl Dihydroxy Derivatives Through Molecular Docking Associated with CoMSIA/HQSAR Models^†[J]. Chem. J. Chinese Universities, 2018, 39(2): 299.

Figures/Tables 11

Table 1 Total score(Kd) of two hydroxy polychlorinated biphenyls

No.	Compound	K_d	Similarity	No.	Compound	K_d	Similarity
1^a	4,5-2OH-CB35	4.32	0.58	16^a	3,4-2OH-CB76	3.53	0.63
$2 a *$	2,3-2OH-CB37	5.56	0.65	17^a	4,5-2OH-CB76	3.41	0.57
3^a	5,6-2OH-CB37	2.03	0.57	18^b	2',3'-2OH-CB77	4.21	0.65
4^b	4',5'-2OH-CB38	4.04	0.56	19^a	2',3'-2OH-CB81	2.74	0.64
5^a	4',5'-2OH-CB55	3.82	0.58	20	5,6-2OH-CB105	0.98	0.39
6^a	4,5-2OH-CB56	4.21	0.58	21^b	4',5'-2OH-CB106	2.95	0.57
7^a	2',3'-2OH-CB60	3.75	0.66	22^a	2',3'-2OH-CB114	2.79	0.64
8^a	5,6-2OH-CB60	1.25	0.55	23^a	5',6'-2OH-CB126	1.13	0.63
9^b	4',5'-2OH-CB61	3.96	0.60	24	5,6-2OH-CB128	0.44	0.37
10^a	3,4-2OH-CB61	3.37	0.60	25	4',5'-2OH-CB129	2.57	0.38
11	5,6-2OH-CB66	2.32	0.39	26	5',6'-2OH-CB137	0.56	0.35
12^a	5',6'-2OH-CB66	2.24	0.63	27	5,6-2OH-CB138	0.90	0.38
13^b	4',5'-2OH-CB67	5.18	0.57	28	3,4-2OH-CB141	1.00	0.39
14^a	3,4-2OH-CB68	2.64	0.62	29	5,6-2OH-CB157	0.81	0.30
15^a	2',3'-2OH-CB74	3.14	0.64	30	2',3'-2OH-CB167	0.24	0.45

Table 1 Total score(Kd) of two hydroxy polychlorinated biphenyls

No.	Compound	K_d	Similarity	No.	Compound	K_d	Similarity
1^a	4,5-2OH-CB35	4.32	0.58	16^a	3,4-2OH-CB76	3.53	0.63
$2 a *$	2,3-2OH-CB37	5.56	0.65	17^a	4,5-2OH-CB76	3.41	0.57
3^a	5,6-2OH-CB37	2.03	0.57	18^b	2',3'-2OH-CB77	4.21	0.65
4^b	4',5'-2OH-CB38	4.04	0.56	19^a	2',3'-2OH-CB81	2.74	0.64
5^a	4',5'-2OH-CB55	3.82	0.58	20	5,6-2OH-CB105	0.98	0.39
6^a	4,5-2OH-CB56	4.21	0.58	21^b	4',5'-2OH-CB106	2.95	0.57
7^a	2',3'-2OH-CB60	3.75	0.66	22^a	2',3'-2OH-CB114	2.79	0.64
8^a	5,6-2OH-CB60	1.25	0.55	23^a	5',6'-2OH-CB126	1.13	0.63
9^b	4',5'-2OH-CB61	3.96	0.60	24	5,6-2OH-CB128	0.44	0.37
10^a	3,4-2OH-CB61	3.37	0.60	25	4',5'-2OH-CB129	2.57	0.38
11	5,6-2OH-CB66	2.32	0.39	26	5',6'-2OH-CB137	0.56	0.35
12^a	5',6'-2OH-CB66	2.24	0.63	27	5,6-2OH-CB138	0.90	0.38
13^b	4',5'-2OH-CB67	5.18	0.57	28	3,4-2OH-CB141	1.00	0.39
14^a	3,4-2OH-CB68	2.64	0.62	29	5,6-2OH-CB157	0.81	0.30
15^a	2',3'-2OH-CB74	3.14	0.64	30	2',3'-2OH-CB167	0.24	0.45

Fig.1 Binding pattern diagram of 2,3-2OH-CB37(A), 3,4-2OH-CB61(B), 4,5-2OH-CB35(C) and 5,6-2OH-CB37(D) with BphcThe three-dimensional structure of IKW6 represented by the ribbon structure, docking ligands and amino acid residues represented by the stick model, hydrogen bond represented by yellow dashed lines.

Table 2 Primary parameters of the internal and external validation for CoMSIA model

No.	Internal validation					External validation
No.	n	q²	r²	SEE	F	$r pred 2$	SEP	$Q ext 2$
1	5	0.569	0.985	0.134	108.792	0.982	0.135	0.779
2	7	0.566	0.985	0.136	133.500	0.935	0.273	0.824
3	5	0.553	0.983	0.137	102.504	0.945	0.327	0.745
4	6	0.535	0.973	0.150	133.385	0.931	0.328	0.801
5	6	0.574	0.984	0.128	101.032	0.977	0.172	0.771
6	6	0.501	0.994	0.132	104.524	0.965	0.154	0.682
7	7	0.598	0.980	0.126	112.334	0.982	0.163	0.679
8	6	0.624	0.962	0.142	124.231	0.973	0.182	0.724
9	5	0.572	0.986	0.156	141.529	0.932	0.209	0.754
10	7	0.529	0.991	0.134	105.010	0.967	0.311	0.593
11	6	0.535	0.990	0.145	131.204	0.985	0.345	0.628
12	7	0.567	0.968	0.127	112.574	0.971	0.178	0.721

Table 2 Primary parameters of the internal and external validation for CoMSIA model

No.	Internal validation					External validation
No.	n	q²	r²	SEE	F	$r pred 2$	SEP	$Q ext 2$
1	5	0.569	0.985	0.134	108.792	0.982	0.135	0.779
2	7	0.566	0.985	0.136	133.500	0.935	0.273	0.824
3	5	0.553	0.983	0.137	102.504	0.945	0.327	0.745
4	6	0.535	0.973	0.150	133.385	0.931	0.328	0.801
5	6	0.574	0.984	0.128	101.032	0.977	0.172	0.771
6	6	0.501	0.994	0.132	104.524	0.965	0.154	0.682
7	7	0.598	0.980	0.126	112.334	0.982	0.163	0.679
8	6	0.624	0.962	0.142	124.231	0.973	0.182	0.724
9	5	0.572	0.986	0.156	141.529	0.932	0.209	0.754
10	7	0.529	0.991	0.134	105.010	0.967	0.311	0.593
11	6	0.535	0.990	0.145	131.204	0.985	0.345	0.628
12	7	0.567	0.968	0.127	112.574	0.971	0.178	0.721

Fig.2 Contour maps for CoMSIA model for 2',3'-2OH-CB37 of electrostatic(A), steric(B) and hydrogen donor(C)

Fig.3 Contour maps for electrostatic for 2',3'-2OH-CB60(A) and 2',3'-2OH-CB114(B)

Table 3 HQSAR model for distinguishing parameters of different fragments

Model	Fragment distinction	Fragment size	r²	q²	$r pred 2$	SEE	n	HL
1	A/B/C	4—7	0.976	0.867	0.912	0.243	6	59
2	A/B/C/H	4—7	0.987	0.926	0.924	0.172	6	59
3	A/B/C/Ch	4—7	0.976	0.867	0.912	0.241	6	59
4	A/B/C/DA	4—7	0.923	0.782	0.896	0.386	4	71
5	A/B/C/H/Ch	4—7	0.987	0.926	0.924	0.173	6	59
6	A/B/C/H/DA	4—7	0.989	0.900	0.935	0.164	6	59
7	A/B/C/Ch/DA	4—7	0.958	0.806	0.900	0.301	6	59
8	A/B/C/H/Ch/DA	4—7	0.980	0.852	0.913	0.204	6	59

Table 3 HQSAR model for distinguishing parameters of different fragments

Model	Fragment distinction	Fragment size	r²	q²	$r pred 2$	SEE	n	HL
1	A/B/C	4—7	0.976	0.867	0.912	0.243	6	59
2	A/B/C/H	4—7	0.987	0.926	0.924	0.172	6	59
3	A/B/C/Ch	4—7	0.976	0.867	0.912	0.241	6	59
4	A/B/C/DA	4—7	0.923	0.782	0.896	0.386	4	71
5	A/B/C/H/Ch	4—7	0.987	0.926	0.924	0.173	6	59
6	A/B/C/H/DA	4—7	0.989	0.900	0.935	0.164	6	59
7	A/B/C/Ch/DA	4—7	0.958	0.806	0.900	0.301	6	59
8	A/B/C/H/Ch/DA	4—7	0.980	0.852	0.913	0.204	6	59

Fig.4 Electrostatic potential map(A) and activity contribution diagram(B) of 5,6-2OH-CB60

Table 4 Frequency and total score of new 5,6-2OH-CB60 molecules

No.			Frequency/cm^-1		K_d		Similarity		Change rate of K_d(%)
Target molecule			36.46		1.25		0.55
1			38.09		2.42		0.61		94
2			38.49		2.30		0.54		84
3			36.68		2.06		0.51		65
4					0.92		0.05
5			30.09		2.40		0.55		92
No.	Compound	Frequency/cm^-1		K_d		Similarity		Change rate ofK_d(%)
6		24.94		2.32		0.53		86
7				0.27		0.55
8		34.55		2.13		0.55		70
9		31.54		2.47		0.60		98
10		30.38		3.56		0.58		185

Table 5 IC50, BCF, KOA, t1/2, ΔE and ΔH of new designed 5,6-2OH-CB60 molecules*

No.	Compound	IC₅₀	Change rate of IC₅₀(%)	BCF	Change rate of BCF(%)	K_OA	Change rate of K_OA(%)	t_1/2	Change rate of t_1/2(%)	ΔE/ (kJ·mol^-1)	ΔH/ (kJ·mol^-1)
Target molecule	5,6-2OH-CB60	0.52		5.73		9.23		0.84
1	2-OH-5,6-2OH-CB60	0.17	-67	4.18	-27	9.19	-0.43	0.93	10.7	302.86	-50.09
2	2-NH₂-5,6-2OH-CB60	0.33	-37	4.42	-23	9.13	-1.0	0.83	1.1	738.96	-124.15
3	2-OCH₃-5,6-2OH-CB60	0.47	-10	3.85	-33	9.13	-1.0	0.91	8.3	1178.28	-87.43
4	2-CN-5,6-2OH-CB60
5	2-NHCH₃-5,6-2OH-CB60	0.81	56	4.96	-13	9.22	-0.11	0.87	3.5	728.56	-137.60
6	2-CH₂CH₃-5,6-2OH-CB60	0.41	-21	4.66	-19	9.59	3.9	0.88	4.7	1159.13	-168.75
7	2-CH₃-5,6-2OH-CB60
8	2-NO-5,6-2OH-CB60	0.65	25	5.49	4	9.37	1,5	0.72	-14.2	743.19	-297.07
9	2-CHO-5,6-2OH-CB60	0.089	-83	4.78	-17	9.10	1.4	0.89	5.9	967.69	-98.11
10	2-COOH-5,6-2OH-CB60	0.13	-75	4.35	-24	9.32	0.97	0.84	0	854.45	-178.76

Scheme 1 Synthesis path of new 5,6-2OH-CB60 molecules

Scheme 2 Full path inference of 2-OH-5,6-2OH-CB60ΔE/(kJ·mol-1): Energy barrier; ΔH(kJ·mol-1): reaction heats.

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