Pharmacophore generation and atom-based 3D-QSAR of novel quinoline-3-carbonitrile derivatives as Tpl2 kinase inhibitors

Figures & data

Table 1.  Tpl2 kinase inhibition data of quinoline-3-carbonitrile and their analogues.

S.No	R1	R2	R3	A	pIC50
1		-CH3	-H	C	4.398
2		-H	-H	C	6
3		-H	-H	C	6.745
4		-H	-H	C	7.721
5		-H	-H	C	4.939
6		-H	-CH3	C	4.721
7		-H	-H	C	7.131
8		-H	-H	N	6.854
9		-H	-H	C	7
10		-H	-H	C	6.194
11		-H	-H	C	4.398
12		-H	-H	C	5.658
13		-H	-H	C	7.854
14		-H	-H	C	8.523
15		-H	-H	C	5
16		-H	-H	C	5.155
17		-H	-H	C	6.678
19		-H	-H	C	6.959
20			-H	C	5.036
21		-H	-H	N	6.886
22			-H	C	4.398
23		-H	-H	C	7.509
24		-H	-H	C	6.62
25			-H	C	4.398
26		-H	-H	C	4.959
27		-H	-H	C	7.222
28		-H	-H	C	6.854
30		-H	-H	C	7.046
31		-H	-H	C	6.585
32		-H	-H	C	6.699
34		-H	-OH	C	4.398
35		-H	-H	N	5.921
36		-H	-H	C	8.523
37		-H	-H	C	6.959
38		-H	-H	C	4.523
S.No	R1	XX	XX	A	pIC50
18	-CH3	XX	XX	N	4.398
29	-H	XX	XX	S	5
33	-H	XX	XX	O	4.398

Figure 1.  Common pharmacophore for active ligands (three aromatic rings (grey circle)), one H-donor (blue sphere with single arrow) and one acceptor (pink sphere with one arrow).

Table 2.  The scores of different parameters of the ADRRR hypothesis.

ID	Survival	Survival-inactive	Site	Vector	Volume	Selectivity	Matches	Energy	Activity	Inactive
ADRRR	3.518	1.276	0.84	0.96	0.716	1.744	9	0.661	7.046	2.243

Figure 2.  Common pharmacophoric sites of active ligands with distance.

Table 3.  PLS statistical parameters of the selected 3D-QSAR model.

ID	PLS factors	SD	R-squared	F	P	RMSE	Q-squared	Pearson-R
ADRRR	1	0.668	0.734	68.8	1.203e–008	0.874	0.5388	0.8996
	2	0.426	0.896	103.3	1.615e–012	0.678	0.7223	0.9123
	3	0.331	0.940	119.3	3.655e–014	0.601	0.782	0.9203
	4	0.276	0.96	131.9	4.871e–015	0.584	0.7945	0.9088

SD, standard deviation of the regression; R, squared value of R² for the regression; F, variance ratio.

Large values of F indicate a more statistically significant regression; P, significance level of variance ratio. Smaller values indicate a greater degree of confidence; RMSE, root-mean-square error; Q, squared value of Q² for the predicted activities; Pearson-R, Pearson-R value for the correlation between the predicted and observed activity for the test set.

Table 4.  Fitness and predicted activity data for the test and training set of compounds.

Ligand name	QSAR Set	Activity	PLS factors	Predicted activity	Pharm set	Fitness
1	Training	4.398	4	4.59	Inactive	2.49
3	Training	6.745	4	6.04		2.18
4	Training	7.721	4	7.52	Active	2.38
5	Training	4.939	4	4.88		2.46
6	Training	4.721	4	4.76		2.26
7	Training	7.131	4	6.92	Active	2.74
9	Training	7	4	6.97	Active	2.43
11	Training	4.398	4	4.31	Inactive	1.92
12	Training	5.658	4	5.77		1.35
13	Training	7.854	4	7.91	Active	2.25
16	Training	5.155	4	6.04		2.18
17	Training	6.678	4	6.61		2.83
19	Training	6.959	4	6.87		2.42
20	Training	5.036	4	5.16		2.42
21	Training	6.886	4	6.86		2.13
22	Training	4.398	4	4.27	Inactive	2.38
24	Training	6.62	4	6.74		2.64
25	Training	4.398	4	4.34	Inactive	2.37
26	Training	4.959	4	5.01		1.52
27	Training	7.222	4	7.02	Active	2.57
28	Training	6.854	4	6.86		2.64
31	Training	6.585	4	6.67		2.48
32	Training	6.699	4	7.02		2.55
34	Training	4.398	4	4.4	Inactive	2.26
35	Training	5.921	4	5.97		2.03
36	Training	8.523	4	8.52	Active	2.56
38	Training	4.523	4	4.37		2.22
2	Test	6	4	5.39		2.23
8	Test	6.854	4	6.99		2.08
10	Test	6.194	4	6.26		2.52
14	Test	8.523	4	8.17	Active	2.57
15	Test	5	4	5.73		2
18	Test	4.398	4	5.15	Inactive	2.11
23	Test	7.509	4	7.15	Active	2.75
29	Test	5	4	4.9		2.15
30	Test	7.046	4	7.16	Active	3
33	Test	4.398	4	5.69	Inactive	2.17
37	Test	6.959	4	6.39		2.43

Figure 3.  Alignment of active and inactive ligands to the pharmacophore.

Figure 4.  Fitness graph between observed activity vs. Phase predicted activity for training and test set compounds.

Figure 5.  QSAR visualization of various substituents effect: (A) Electron withdrawing feature, (B) Hydrogen-bond donor, (C) Hydrophobic features, (D) Positive ionic and (E) Negative ionic.

Table 5.  The ROC and a few performance measures derived from the number of true positives, true negatives, false positives and false negatives by confusion matrix.

Number of total cases used	Number of cases correctly detected	Accuracy	Sensitivity	Specificity	Empiric ROC area
100	98	98.0%	97.1%	98.5%	0.978

Figure 6.  The ROC curve between the true positive fraction and false positive fraction.

Figure 7.  The structure of six potential Tpl2 kinase inhibitors with their Asinex ID, fitness value and predicted activity.