Prediction of HIV-1 protease inhibitory activity of 4-hydroxy-5,6-dihydropyran-2-ones: QSAR study

Figures & data

Table 1.   Structure, selected parameters, and their HIV-1 protease inhibitory activity of 4-hydroxy-5,6-dihydropyran-2-one analogues.

Compound No.	N	R	R’	R”	logP	IR	IR′
1^a	1	H	H	H	2.356	0.000	0.000
2	1	C3H7	H	H	3.299	0.000	0.000
3	1	C4H9	H	H	3.695	0.000	0.000
4	1	C5H11	H	H	4.091	0.000	0.000
5	1	C6H13	H	H	4.488	0.000	0.000
6	1	CH2CHMe2	H	H	3.629	0.000	0.000
7	1	CH2CH2CHMe2	H	H	4.026	0.000	0.000
8	1	CH2CH2CH2CHMe2	H	H	4.422	0.000	0.000
9	1	CH2-c-pentyl	H	H	3.918	0.000	0.000
10	1	CH2-c-hexyl	H	H	4.314	0.000	0.000
11	1	C6H5	H	H	3.868	0.000	0.000
12	1	(CH2)2C6H5	H	H	4.516	1.000	0.000
13^a	0	CH2CH2CH2CHMe2	H	H	4.327	0.000	0.000
14	0	C6H5	H	H	3.773	0.000	0.000
15	0	(CH2)2C6H5	H	H	4.421	1.000	0.000
16	2	H	H	H	2.607	0.000	0.000
17^a	2	C3H7	H	H	3.550	0.000	0.000
18	2	C4H9	H	H	3.947	0.000	0.000
19	2	C5H11	H	H	4.343	0.000	0.000
20	2	C6H13	H	H	4.739	0.000	0.000
21^a	2	CH2CHMe2	H	H	3.881	0.000	0.000
22	2	CH2CH2CHMe2	H	H	4.277	0.000	0.000
23	2	CH2CH2CH2CHMe2	H	H	4.673	0.000	0.000
24	2	CH2-c-pentyl	H	H	4.169	0.000	0.000
25	2	C6H5	H	H	4.120	0.000	0.000
26	2	(CH2)2C6H5	H	H	4.768	1.000	0.000
27	0	C6H5	H	H	3.773	0.000	0.000
28	0	C6H5	Me	H	4.240	0.000	1.000
29	0	C6H5	CHMe2	H	4.967	0.000	1.000
30	0	C6H5	CHMeEt	H	5.363	0.000	1.000
31	0	C6H5	c-Pentyl	H	5.256	0.000	1.000
32	0	C6H5	c-Hexyl	H	5.652	0.000	1.000
33	0	C6H5	CMe3	H	5.400	0.000	1.000
34	0	C6H5	CHMe2	Me	5.434	0.000	1.000
35	0	C6H5	CHMe2	CHMe2	5.830	0.000	1.000
36^a	0	C6H5	CMe3	Me	5.867	0.000	1.000
37	0	(CH2)2 C6H5	H	H	4.025	1.000	0.000
38	0	(CH2)2 C6H5	Me	H	4.492	1.000	1.000
39	0	(CH2)2 C6H5	CHMe2	H	5.219	1.000	1.000
40	0	(CH2)2 C6H5	CHMeEt	H	5.615	1.000	1.000
41	0	(CH2)2 C6H5	c-Pentyl	H	5.904	1.000	1.000
42^a	0	(CH2)2 C6H5	c-Hexyl	H	5.952	1.000	1.000
43	0	(CH2)2 C6H5	CMe3	Me	5.686	1.000	1.000
44	0	(CH2)2 C6H5	CHMe2	CHMe2	6.413	1.000	1.000
45	0	(CH2)2 C6H5	CHMe2	Me	6.119	1.000	1.000
46	0	(CH2)2 C6H5	CMe3	CHMe2	6.846	1.000	1.000
47	0	(CH2)2 C6H5	CHMe2	Me	5.686	1.000	1.000
48	2	(CH2)2COOH	H	H	2.351	0.000	0.000
49	2	(CH2)3COOH	H	H	2.768	0.000	0.000
50	2	(CH2)4COOH	H	H	3.185	0.000	0.000
51	2	(CH2)3CONH2	H	H	2.117	0.000	0.000
52	2	(CH2)4CONH2	H	H	2.535	0.000	0.000
53^a	2	4-Pyridyl	H	H	2.908	0.000	0.000
54	2	CH2N(Me)C6H5	H	H	3.587	0.000	0.000
55	1	CH2OC6H5	H	H	3.896	0.000	0.000
56	1	(CH2)4OH	H	H	2.275	0.000	0.000
57	1	(CH2)2−	H	H	2.597	0.000	0.000
58^a	1	(CH2)3−	H	H	3.654	0.000	0.000
59^a	1	(CH2)4CH3−	H	H	2.374	0.000	0.000

IR, if the substituent at R is –(CH₂)₂C₆H₅ then the value of IR is 1 otherwise 0); IR′, if any substituent is present at R’ then the value of IR′ is 1 otherwise 0.

^aTest set compounds.

Table 2.   Calculated and predicted (LOO) activities of training and test set using equation 5 and 6.

Compound No.	Observed activity (M)^a	pIC50 (M)
		Equation 5		Equation 6
		Cal. Act.	Pred. Act.	Cal. Act.	Pred. Act.
1^b	5.05	5.924	—	5.961	—
2	6.54	6.5	6.498	6.518	6.517
3	6.57	6.695	6.699	6.68	6.685
4	6.91	6.863	6.861	6.801	6.796
5	6.74	7.004	7.014	6.878	6.886
6	6.36	6.664	6.675	6.656	6.667
7	7.01	6.837	6.831	6.784	6.775
8	6.74	6.983	6.992	6.868	6.875
9	7.06	6.793	6.783	6.753	6.742
10	6.86	6.946	6.949	6.85	6.849
11	6.58	6.772	6.778	6.738	6.744
12	7.22	7.013	7.006	6.882	6.862
13^b	5.85	6.940	—	6.852	—
14	6.96	6.73	6.722	6.708	6.698
15	6.89	6.983	6.986	6.868	6.867
16	5.68	6.093	6.141	6.131	6.184
17^b	5.29	6.618	—	6.626	—
18	6.40	6.805	6.819	6.762	6.776
19	7.08	6.956	6.951	6.855	6.844
20	6.95	7.08	7.085	6.905	6.902
21^b	5.92	6.767	—	6.741	—
22	7.02	6.933	6.930	6.842	6.834
23	6.81	7.061	7.071	6.9	6.907
24	6.29	6.893	6.914	6.819	6.842
25	6.82	6.874	6.876	6.808	6.807
26	7.29	7.088	7.079	6.907	6.875
27	6.96	6.73	6.722	6.708	6.698
28	6.41	6.919	6.938	6.835	6.854
29	7.64	7.139	7.114	7.418	7.382
30	7.77	7.22	7.175	7.401	7.354
31	7.85	7.201	7.155	7.41	7.352
32	6.90	7.262	7.310	7.362	7.431
33	7.31	7.226	7.219	7.397	7.408
34	7.42	7.231	7.214	7.393	7.390
35	6.92	7.281	7.348	7.326	7.404
36^b	7.92	8.118	—	7.875	—
37	6.89	6.837	6.835	7.286	7.432
38	7.14	7.547	7.691	7.433	7.546
39	7.85	7.735	7.712	7.966	8.000
40	8.00	7.798	7.771	7.923	7.910
41	7.49	7.828	7.870	7.864	7.911
42^b	8.52	8.124	—	7.347	—
43	8.15	7.807	7.762	7.91	7.875
44	7.85	7.845	7.843	7.705	7.669
45	8.00	7.84	7.818	7.805	7.777
46	7.33	7.823	8.094	7.514	7.674
47	8.22	7.807	7.752	7.91	7.864
48	5.92	5.922	5.922	5.955	5.961
49	6.57	6.195	6.162	6.232	6.202
50	8.30	*	*	*	*
51	5.89	5.755	5.714	5.778	5.744
52	6.47	6.046	5.990	6.083	6.031
53^b	6.10	6.637	—	6.640	—
54	6.76	6.784	6.293	6.747	6.330
55	5.64	5.928	6.784	5.532	6.746
56	5.90	5.869	5.862	5.899	5.899
57	4.93	*	*	*	*
58b	6.49	6.666	–	6.663	–
59b	5.64	5.931	–	5.968	–

Cal. Act., calculated activity; LOO, leave one out; Pred. Act., predicted activity (LOO).

^aThe experimental IC₅₀ values (in nano molar) were converted into –logIC₅₀ (pIC₅₀, in molar).

^bTest set compound.

*Outlier.

Table 3.   Correlation matrix of physico-chemical descriptors and HIV protease inhibitory activity.

	pIC50	logP	logP^2	IR	IR′	VIF
						Equation 5	Equation 6
pIC50	1	1	1	1	1	—	—
logP	0.750	0.987	0.652	0.571		—	—
logP^2	0.723	0.600				—	—
IR	0.561	0.714	0.725			2.019	2.021
IR′	0.641					—	2.133

IR, if the substituent at R is –(CH₂)₂C₆H₅ then the value of IR is 1 otherwise 0); IR′, if any substituent is present at R’ then the value of IR′ is 1 otherwise 0; VIF, variance inflation factor.