QSAR and pharmacophore modeling of aminopyridazine derivatives of γ-aminobutyric acid as selective GABA-A receptor antagonists against induced coma

Figures & data

Table 1 Biological activity data

Compound number	Substituents				Ki (μΜ)	pKi
	R	R1	R2	R3
1	(CH2)3CO2H	CH3	H	C6H5	2.3	−0.361
2^a	(CH2)3CONH2	CH3	H	C6H5	91	−1.959
3	(CH2)3C≡N	CH3	H	C6H5	20	−1.301
4	CH2 CO2H	CH3	H	C6H5	62	−1.792
5	(CH2)2CO2H	CH3	H	C6H5	7	−0.845
6	(CH2)4CO2H	CH3	H	C6H5	10	−1.000
7^a	(CH2)5CO2H	CH3	H	C6H5	12.7	−1.103
8	(CH2)2CH(CH3)CO2H	CH3	H	C6H5	7	−0.845
9	CH(CH3)(CH2)2CO2H	CH3	H	C6H5	9	−0.954
10^a	(CH2)3CO2H	H	H	C6H5	1.22	−0.086
11^b	(CH2)3CO2H	C6H5	H	C6H5	100	−2.000
12	(CH2)3CO2H	H	CH3	C6H5	10.4	−1.017
13^a	(CH2)3CO2H	H	C6H5	H	100	−2.000
14	(CH2)3CO2H	H	C6H5	H	10.6	−1.025
15^a	(CH2)3CO2H	CH3	H	H	31.9	−1.503
16	(CH2)3CO2H	H	H	(CH3)2CHCH2	22.3	−1.348
17	(CH2)3CO2H	H	H	C-C6H11	3.74	−0.572
18^a	(CH2)3CO2H	H	H	Cl	91.2	−1.959
19^a	(CH2)3CO2H	H	H	α-THIENYL	0.58	0.236
20	(CH2)3CO2H	H	H	β-THIENYL	2.37	−0.374
21	(CH2)3CO2H	CH3	H	α-NAPHTHYL	2.64	−0.421
22	(CH2)3CO2H	H	H	2-Cl-C6H4
23	(CH2)3CO2H	CH3	H	2-Cl-C6H4
24^a	(CH2)3CO2H	CH3	H	3-Cl-C6H4
25	(CH2)3CO2H	H	H	4-Cl-C6H4	0.28	0.552
26^a	(CH2)3CO2H	H	H	2,4,Cl2C6H3	0.56	0.251
27^a	(CH2)3CO2H	H	H	4-F-C6H4	1.27	−0.103
28	(CH2)3CO2H	H	H	4-NO2C6H4	1.37	−0.136
29	(CH2)3CO2H	CH3	H	4-NO2C6H4	22.8	−1.357
30	(CH2)3CO2H	H	H	4-CH3O-C6H4	0.15	0.823
31^a	(CH2)3CO2H	CH3	H	4-CH3O-C6H4	0.31	0.508
32^a	(CH2)3CO2H	CH3	H	4-OH-C6H4	0.43	0.366
33	(CH2)3CO2H	CH3	H	4-CH3-C6H4	0.55	0.259

Note:

a Test set;

b outlier.

Table 2 Molecular descriptors used in this study

Descriptor classes	Descriptor names
Constitutional descriptors	Number of rotatable bonds, fraction of rotatable bonds, number of rigid bonds, number of rings, number of single bonds, number of double bonds, number of H-bond acceptors, number of H-bond donors, number of amino groups tertiary, number of amide groups, number of ester groups, number of halogen atoms, molecular mass, number of total atoms, and ratio of donors to acceptor
Geometrical descriptors	2D-VSA hydrophobic_unsat, 2D-VSA other, 2D-VSA polar, fraction of 2D-VSA polar, 2D-VSA Hbond, 2D-VSA Hbond donor, 2D-VSA Hbond all, fraction of 2D-VSA Hbond, topological PSA, 2D-VDW surface, 2D-VDW volume, 2D-VSA hydrophobic, fraction of 2D-VSA hydrophobic, 2D-VSA hydrophobic_sat, and number of stereo centers
Physicochemical descriptors	Polarizability_Miller, SKlogP value, water solubility, vapor pressure, buffer solubility, SK_MP, AMR value (calculated molecular refractivity index), Polarizability_MPEOE, SKlogs value, SKlogPvp, SKlogs_buffer, SK_BP, solvation-free energy, AlogP98 value, AlogP98 002C, AlogP98 006C, AlogP98 008C, AlogP98 016C, AlogP98 017C, AlogP98 019C, AlogP98 041C, AlogP98 047η, AlogP98 067N, AlogP98 073N, AlogP98 075N, AlogP98 094Br, AlogP98 084F, AlogP98 089Cl, AlogP98 094Br, AlogP98 001C, AlogP98 003C, AlogP98 005C, AlogP98 046H, AlogP98 050H, AlogP98 052H, AlogP98 056O, AlogP98 058O, AlogP98 059O, AlogP98 060O, AlogP98 068N, and AlogP98 072N

Figure 1 Normal probability distribution of the residuals.

Figure 2 Residual versus fitted plot of the response data.

Table 3 Calculated structural invariants of a series of aminopyridazine derivatives of γ-aminobutyric acid

Comp no	Calculated structural properties
	No of H-bond acceptors	No of H-bond donors	AlogP98	SKlogS (mol/L)	Molecular PSA (Å^2)	Molecular volume (Å^3)	Molecular weight	No of stereo centers
1	3	4	2.32	−2.10	63.92	287.75	308.789	1
2	2	4	1.79	−2.62	68.92	295.37	273.00	1
3	1	3	2.25	−2.94	53.02	288.92	334.24	1
4	3	3	1.56	−2.16	63.94	253.16	245.282	1
5	3	4	1.84	−2.01	63.92	269.84	339.219	1
6	3	4	2.80	−2.52	63.92	305.65	322.816	1
7	3	4	3.28	−2.97	63.92	323.56	381.300	1
8	3	4	2.63	−2.57	63.94	302.88	367.273	2
9	3	4	2.77	−2.95	62.43	301.21	363.273	2
10	3	4	2.15	−2.39	62.21	262.73	339.219	1
11	3	4	3.54	−3.44	63.64	337.7	370.860	1
12	3	4	2.25	−2.29	61.41	281.77	353.246	1
13	3	4	1.96	−2.88	62.17	262.21	294.762	1
14	3	4	2.26	−2.30	60.58	279.50	353.246	1
15	3	4	1.25	−1.04	64.74	215.24	271.148	1
16	3	4	2.24	−2.08	62.38	261.98	319.229	1
17	3	4	2.58	−2.12	62.40	291.03	345.267	1
18	3	4	1.25	−1.47	63.15	205.14	253.109	1
19	3	4	2.02	−1.92	63.23	256.49	345.245	1
20	4	4	1.82	−2.48	63.23	258.48	345.245	1
21	3	4	3.77	−4.10	28.52	337.08	358.849	1
22	3	4	2.74	−2.87	62.21	278.05	373.664	1
23	3	4	2.91	−2.58	63.92	303.07	343.234	1
24	3	4	3.03	−3.03	63.92	305.01	343.234	1
25	3	4	2.86	−3.33	62.21	279.92	329.260	1
26	3	4	3.46	−3.77	61.17	295.32	363.652	1
27	3	4	2.42	−2.89	62.21	268.64	312.152	1
28	5	5	1.74	−2.89	100.47	292.93	384.216	1
29	5	5	1.91	−2.60	102.18	317.94	353.786	1
30	4	4	2.24	−2.65	69.75	294.57	369.245	1
31	4	4	2.41	−2.38	71.46	319.59	383.272	1
32	4	5	2.06	−1.96	81.53	298.29	324.788	1
33	3	4	2.72	−2.56	63.92	308.69	322.816	1

Abbreviation: PSA, polar surface area.

Table 4 T-values of the modeled parameters

Predictor variables	T	|T|
No of H-bond acceptors	1.17	1.17
No of H-bond donors	-0.32	0.32
AlogP98	1.67	1.67
SKlogS	0.60	0.60
Topological PSA	0.29	0.29
Molecular volume	−0.89	0.89
Molecular weight	1.71	1.71
No of stereo centers	−1.31	1.31

Abbreviation: PSA, polar surface area.

Figure 3 Plot of observed versus predicted binding affinity of the test compounds.

Figure 4 Pharmacophore model of highly active compounds.

Figure 5 Pharmacophore model of low active compound number 11.

Abbreviations: H AR, hydrophobicity and aromaticity; HBD, hydrogen bond donor; HBA, hydrogen bond acceptor; NI, negative ionization.

Figure 6 Best pose of highly active ligand 30 (stick model) docked with the human GABA-A target cavity represented by molecular surface.

Notes: The active residues within 4 Å of the inhibitor are displayed. Green color dotted lines represent H-bonding.

Figure 7 Structural requirements for designing highly active congeneric compounds.

Abbreviations: H AR, hydrophobicity and aromaticity; HBD, hydrogen bond donor; HBA, hydrogen bond acceptor; NI, negative ionization.