Pharmacophore modelling and atom-based 3D-QSAR studies on N-methyl pyrimidones as HIV-1 integrase inhibitors

Figures & data

Table 1.  Structures and actual versus predicted pIC₅₀ of compounds 1-39.

Compound	R	Actual pIC50	Predicted pIC50	Residuals
1*		7.20	7.32	–0.12
2		6.14	6.22	–0.08
3		8	7.83	0.17
4		6.16	6.18	–0.02
5		7	7.19	–0.19
6		6.74	7.04	–0.3
7		6.69	6.86	–0.17
8		6.88	6.79	0.09
9		7.52	7.61	–0.09
10		7.21	7.34	–0.13
11		7.69	7.36	0.33
12		7.69	7.35	0.34
13		7.52	7.57	–0.05
14		6.67	6.76	–0.09
15		7.67	7.57	0.1
16		7.20	7.46	–0.26
17		7.22	7.34	–0.12
18		7.15	7.19	–0.04
19*		7.43	7.25	0.18
20*		6.85	6.87	–0.02
21		7	6.86	0.14
22		7.30	7.13	0.17
23		6.69	6.77	–0.08
24*		6.60	6.87	–0.27
25		6.88	6.90	–0.02
26		7.38	7.35	0.03
27		7.49	7.39	0.1
28		5.39	5.39	0
29		7.92	7.90	0.02
30		8.39	8.49	–0.1
31		7.28	7.21	0.07
32		7.95	7.95	0
33		8.15	8.20	–0.05
34*		8.09	7.86	0.23
35		7.30	7.37	–0.07
36		7.48	7.48	0
37		7.82	8.00	–0.18
38*		7.69	7.54	0.15
39*		7.82	7.30	0.52

*Compounds used for test set.

Table 2.  Structures and actual versus predicted pIC₅₀ of compounds 40–50.

Compound	R1	R2	N	Actual pIC50	Predicted pIC50	Residuals
40	H	H	1	7.18	7.27	–0.09
41	H	H	2	7.14	7.01	0.13
42	2-F	H	1	6.75	6.87	–0.12
43*	3-F	H	1	7.20	7.29	–0.09
44	3-Cl	H	1	7.20	7.44	–0.24
45	3-Br	H	1	7.72	7.31	0.41
46*	3-OMe	H	1	6.85	7.04	–0.19
47*	4-F	3-F	1	7.67	7.36	0.31
48	4-F	3-Me	1	7.06	7.04	0.02
49	4-F	3-Cl	1	7.55	7.51	0.04
50	4-F	3-Br	1	7.35	7.23	0.12

*Compounds used for test set.

Table 3.  Quantitative Structure Activity Relationship (QSAR) results for the three best Common Pharmacophore Hypotheses (CPHs).

	AADDR	AADRR	AADHR
SD	0.16	0.13	0.13
r^2	0.92	0.94	0.95
F	84.8	127.5	129.5
P	3.294e–018	5.129e–021	4e–021
RMSE	0.06	0.38	0.33
Q^2	0.71	0.29	0.46
Pearson R	0.90	0.61	0.69

SD =  Standard deviation of the regression, r² = correlation coefficient, F =  variance ratio, p = significance level of variance ratio, RMSE = root mean-square error, Q² = predictive coefficient of the test set, Pearson R = Correlation between the predicted and observed activity for the test set.

Figure 1.  Common pharmacophore model alignment of active compounds. Spheres with vectors A4 and A5 are acceptor features, sphere R11 is aromatic ring feature and spheres with vectors D7 and D8 are represents donor features.

Figure 2.  Scatter plot for the predicted and actual pIC₅₀ values for AADDR hypothesis applied to (a) the training set (r² = 0.92, SD = 0.16, F = 84.8, N = 40) and (b) the test set (Q² = 0.71, RMSE = 0.06, Pearson R = 0.90, N = 10).