Hologram quantitative structure–activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors

Figures & data

Table 1 Chemical structures and biological data of 42 tricyclic phthalimide HIV-1 integrase inhibitors

Notes: *Test set compounds. pIC₅₀ represents the -log Ic₅₀, where IC₅₀ is the half maximal inhibitory concentration.

Abbreviation: HIV, Human immunodeficiency virus.

Table 2 Summary of hologram quantitative structure–activity relationship (HQSAR) statistical indexes for the influence of various fragment distinctions (FD), using 4–7 as the fragment size parameter

Model	FD	Statistical indexes
		q ^2	r ^2	SEcv	PC	HL
1	A	0.765	0.965	0.370	6	97
2	B	0.362	0.668	0.574	3	97
3	C	0.517	0.918	0.520	5	97
4	H	0.258	0.465	0.608	2	97
5	DA	0.625	0.889	0.458	5	199
6	A/B	0.644	0.963	0.456	6	59
7	A/C	0.551	0.972	0.512	6	401
8	A/H	0.474	0.942	0.555	6	151
9	A/DA	0.482	0.926	0.550	6	83
10	B/C	0.660	0.976	0.446	6	353
11	B/H	0.362	0.668	0.574	3	97
12	B/DA	0.454	0.959	0.553	5	307
13	C/H	0.517	0.918	0.520	5	97
14	C/DA	0.250	0.474	0.600	1	401
15	A/B/C	0.649	0.959	0.453	6	61

Note: Models 1, 10 and 15 are indicated in bold to show that they are the three best models using 4–7 as the fragment size parameter.

Abbreviations: A, atoms; B, bonds; C, connectivity; DA, donor/acceptor atoms; H, hydrogen; HL, hologram length; PC, principal components; q ², leave-one-out cross-validated correlation coefficient; r ², non-cross-validated correlation coefficient; SE_cv, cross-validated standard error.

Figure 1 Selected atoms to alignment I (A) and three-dimensional (3D) view of superimposed aligned molecules (B). Selected atoms to alignment II (C) and 3D view of superimposed aligned molecules (D).

Table 3 Summary of hologram quantitative structure–activity relationship statistical indexes for the influence of various fragment sizes (FS), using atoms (Models 16–21); bonds and connectivity (Models 22–27); or atoms, bonds, and connectivity (Models 28–33) as the fragment distinction parameter

Model	FS	Statistical indexes
		q ^2	r ^2	SEcv	PC	HL
16	2–5	0.568	0.905	0.502	6	257
17	3–6	0.706	0.927	0.639	5	401
18	4–7	0.765	0.965	0.370	6	97
19	5–8	0.776	0.959	0.362	6	59
20	6–9	0.491	0.956	0.545	6	353
21	7–10	0.611	0.945	0.477	6	59
22	2–5	0.739	0.964	0.391	6	199
23	3–6	0.731	0.972	0.397	6	353
24	4–7	0.660	0.976	0.446	6	353
25	5–8	0.618	0.982	0.472	6	401
26	6–9	0.542	0.978	0.517	6	401
27	7–10	ND	ND	ND	ND	ND
28	2–5	0.802	0.972	0.340	6	61
29	3–6	0.671	0.964	0.438	6	61
30	4–7	0.649	0.959	0.453	6	61
31	5–8	0.599	0.971	0.484	6	83
32	6–9	0.545	0.978	0.516	6	199
33	7–10	0.455	0.976	0.564	6	401

Note: Models 19, 22 and 28 are shown in bold to indicate that they are the three best models in each fragment distinction parameter.

Abbreviations: HL, hologram length; ND, not determined; q ², leave-one-out cross-validated correlation coefficient; r ², non-cross-validated correlation coefficient; PC, principal components; SE_cv, cross-validated standard error.

Table 4 Comparative molecular field analysis for alignments I and II using Tripos standard and indicator force fields with a lattice spacing of 2 Å

PLS statistics	Tripos standard			Tripos indicator
	Probe atom (charge)			Probe atom (charge)
	Csp ^3 (+1)	H (+1)	Osp ^3 (−1)	Csp ^3 (+1)	H (+1)	Osp ^3 (−1)
Alignment I
q ^2	0.588	0.471	0.573	0.625	0.336	0.597
F-value	253.085	333.547	296.312	125.159	56.323	104.418
r ^2	0.957	0.799	0.991	0.973	0.941	0.968
SEE	0.156	0.323	0.073	0.130	0.190	0.142
PC	4	2	6	6	6	6
Alignment II
q ^2	0.557	0.490	0.484	0.748	0.317	0.597
F-value	445.728	361.309	287.329	130.192	55.905	104.418
r ^2	0.992	0.990	0.988	0.974	0.941	0.968
SEE	0.069	0.077	0.086	0.127	0.191	0.142
PC	4	5	5	6	3	6

Abbreviations: PC, principal components; PLS, partial least squares; q ², leave-one-out cross-validated correlation coefficient; r ², non-cross-validated correlation coefficient; SEE, standard error of the estimate.

Table 5 Comparative molecular field analysis for alignment II using lattice spacing of 1 Å and Csp ³ (+1) as the probe atom

PLS statistics	Standard	Indicator
q ^2	0.477	0.583
F-value	675.001	399.966
r ^2	0.995	0.991
SEE	0.056	0.073
PC	3	6

Abbreviations: PC, principal components; PLS, partial least squares; q ², leave-one-out cross-validated correlation coefficient; r ², non-cross-validated correlation coefficient; SEE, standard error of the estimate.

Figure 2 The hologram quantitative structure–activity relationship contribution maps of the most (33) and least (8) potent HIV-1 integrase inhibitors.

Abbreviation: HIV, Human immunodeficiency virus.

Figure 3 Comparative molecular field analysis contour maps for steric field with the most (33; A) and least (8; B) active compounds.

Note: Left images show front view; right images show side view.

Table 6 Experimental and predicted pIC₅₀ values of training and test set compounds

No	Experimental	HQSAR		CoMFA
		Predicted	Residual	Predicted	Residual
1*	4.00	5.95	−1.95	4.12	−0.12
2	6.42	6.35	0.07	ND	ND
3*	6.59	6.63	−0.04	4.00	2.59
4	5.44	5.54	−0.10	ND	ND
5	6.68	6.39	0.29	6.65	0.03
6	4.31	4.40	−0.09	4.22	0.09
7	4.98	4.92	0.06	4.97	0.01
8	4.00	3.92	0.08	4.09	−0.09
9	5.62	5.67	−0.05	5.67	−0.04
10	5.66	5.71	−0.05	5.56	0.10
11	5.98	5.93	0.05	5.90	0.08
12	5.69	5.93	−0.24	5.69	0.00
13	5.00	5.01	−0.01	4.97	0.03
14*	6.25	6.45	−0.20	5.80	0.45
15	5.85	5.93	−0.08	5.83	0.02
16*	6.09	6.23	−0.14	5.53	0.56
17	6.25	6.17	0.08	6.12	0.13
18*	5.70	6.26	−0.56	5.44	0.27
19	6.37	6.35	0.02	6.44	−0.07
20	6.37	6.20	0.17	6.31	0.06
21	6.11	6.24	−0.13	6.13	−0.02
22*	5.80	6.41	−0.61	6.14	−0.34
23	5.69	5.68	0.01	5.81	−0.12
24	6.37	6.35	0.02	6.34	0.03
25*	6.25	6.29	−0.04	6.14	0.11
26	6.38	6.26	0.12	6.04	0.34
27*	6.36	6.53	−0.17	6.15	0.21
28	6.45	6.53	−0.08	6.47	−0.02
29*	6.43	6.47	−0.04	6.18	0.25
30	6.75	6.73	0.02	6.77	−0.01
31*	6.66	6.48	0.18	6.18	0.48
32	6.38	6.43	−0.05	6.53	−0.15
33	6.95	6.95	0.00	7.00	−0.04
34*	6.73	6.79	−0.06	6.57	0.16
35	6.20	6.45	−0.25	6.23	−0.03
36	5.17	5.14	0.03	5.50	−0.33
37	5.85	5.85	0.00	5.79	0.06
38	6.17	6.13	0.04	6.14	0.03
39	6.30	6.14	0.16	6.30	0.00
40	6.00	6.15	−0.15	6.06	−0.06
41*	5.84	6.05	−0.21	6.17	−0.33
42	5.69	5.64	0.05	5.67	0.02

Notes:

* Test set compounds; “ND” indicates that a value was not determined because the molecules did not show any atoms common to the core used for alignment, resulting in the withdrawal of the same training set.

Abbreviations: CoMFA, comparative molecular field analysis; HQSAR, hologram quantitative structure–activity relationship; pIC₅₀, −log IC₅₀; IC₅₀, half maximal inhibitory concentration.

Figure 4 Plot of experimental versus predicted pIC₅₀ values of the training and test sets of the tricyclic phthalimide HIV-1 integrase inhibitors by comparative molecular field analysis (A) and hologram quantitative structure–activity relationship (B).

Abbreviations: pIC₅₀, −log IC₅₀; IC₅₀, half maximal inhibitory concentration; HIV, Human immunodeficiency virus.