Exploring QSAR for CYP11B2 binding affinity and CYP11B2/CYP11B1 selectivity of diverse functional compounds using GFA and G/PLS techniques

Figures & data

Table 1.  Structural features of the diverse compounds having CYP11B2 and CYP11B1 inhibitory activities.

A (Pyridylnaphthalenes)
	X	Y	R	R1	R2	R3	R4	R5
1	CH	CH	-OCH3	H	H	H
2	CH	CH	-OCH3	CH3	H	H
3	CH	CH	-CN	H	H	H
7	CH	CH	-OCH3	H	-CH3	H
8	CH	CH	-CN	H	-CH3	H
9	CH	CH	-OCH3	H	-NH2	H
10^a	CH	CH	-OCH3	H	H	-OH
11^a	CH	CH	-OCH3	H	H	-OCH3
12	CH	CH	-OCH3	CH3	H	-OCH3
14	CH	CH	-OCH3	H	H	-OC2H5
15	CH	CH	-OCH3	H	H	-COOMe
16^a	CH	CH	-OCH3	H	H	-COMe
17^a	CH	CH	-OCH3	H	H	-CH2COOH
18	CH	CH	-OCH3	H	H	-CH2COOMe
19	CH	CH	-OCH3	H	H	-CH2OH
20^a	CH	CH	-OCH3	H	H	-CH2OMe
21	CH	CH	-OCH3	H	-CH2OH	H
22	CH	CH	-OCH3	H	-CH2OMe	H
23	CH	CH	-OCH3	H	H	-CH(OH)Me
24	CH	CH	-OCH3	H	H	-CH(OMe)Me
25	CH	CH	-OCH3	H	H	-Ph
29	CH	CH	H	Benzyl	H	H
30	CH	CH	-OCH3	Benzyl	H	H
31	CH	CH	H	4-Methoxybenzyl	H	H
32^a	CH	CH	H	4-Cyanobenzyl	H	H
33	CH	CH	H	4-Trifluoromethoxybenzyl	H	H
34^a	CH	CH	-OCH3	4-Methoxybenzyl	H	H
35	CH	CH	H	4-Methoxybenzyl	H	-OCH3
36	CH	CH	-OCH3	4-Methoxybenzyl	H	-OCH3
37	CH	CH	-OCH3	Benzyl	H	-OCH3
40	CH	CH	H	4-Methoxybenzoyl	H	H
41	CH	CH	H	3-Fluoro-4-methoxybenzoyl	H	H
42^a	CH	CH	H	4-Cyanobenzoyl	H	H
43	CH	CH	H	4-Trifluoromethoxybenzoyl	H	H
44^a	CH	CH	H	H	H	H
51	CH	CH	-OH	H	H	H
52^a	CH	CH	-Br	H	H	H
53	CH	CH	-OCH3	H	H	H	-Cl	H
54^a	CH	CH	-OCH3	H	H	H	-Br	H
55	-CHCl	CH	H	H	H	H	H	-OCH3
B (Dihydropyridylnaphthalenes)
	S1		S2	S3	S4		Het
4^a	-OCH3		H	H	H		3-Pyridinyl
5	-OCH3			H	H		3-Pyridinyl
6^a	-CN		H	H	H		3-Pyridinyl
13	-OCH3		-CH3	H	H		3-Pyridinyl
28	-OCH3		-CH3	H	H		3-Isoquinolinyl
126	H		H	-CH3	H		3-Pyridinyl
127	H		H	-C2H5	H		3-Pyridinyl
128^a	H		-CH3	H	H		3-Pyridinyl
129	H		H	H	-CH3		3-Pyridinyl
130	H		H	H	-C2H5		3-Pyridinyl
C (Chroman-4-ones)
	S1		S2			S3
45	H		Phenyl
46	H		4-Nitrophenyl
47	H		4-Bromophenyl
48	H		4-Methoxyphenyl
49	-OCH3		Phenyl
50	H		H			4-Nitrophenyl
D (Naphthaleneisoquinolines)
	R1				R2
27	-OCH3				H
28	-OCH3				-CH3
38	H				4-Methoxybenzyl
39^a	-OCH3				4-Methoxybenzyl
E (Dihydronaphthalenes)
	R		R1		Y		Het
56^a	H		-OCH3		CH		1-Imidazolyl
57	H		H		CH		5-Imidazolyl
58	H		H		CH		5-Oxazolyl
F (Heteroarylmethylenetetrahydronaphthalenes)
	R’1		R’2		Het		Isomerism
59	H		H		1-H-Imidazolyl		E
60^a	H		H		1-H-Imidazolyl		Z
63	-CN		H		1-H-Imidazolyl		Z
66^a	H		-Cl		1-H-Imidazolyl		E
75	H		H		3-Pyridinyl		E
76	H		H		3-Pyridinyl		E
85	-OCH3		H		3-Pyridinyl		E
92^a	H		H		4-Pyridinyl		E
101	-OCH3		H		4-Pyridinyl		E
102^a	-OCH3		H		4-Pyridinyl		E
105^a	-OCH3		-OCH3		4-Pyridinyl		E
G (Heteroarylmethyleneindanes)
	R”4	R”5	R”6	R”7	Het		Isomerism
61	H	H	H	H	5-Imidazolyl		E
62	H	H	H	H	5-Imidazolyl		Z
64	H	-CN	H	H	5-Imidazolyl		E
65	H	-CN	H	H	5-Imidazolyl		E
67^a	H	-F	H	H	5-Imidazolyl		E
68	H	-F	H	H	5-Imidazolyl		Z
69^a	H	-Cl	H	H	5-Imidazolyl		E
70	H	-Cl	H	H	5-Imidazolyl		Z
71	H	-Br	H	H	5-Imidazolyl		E
72	H	-Br	H	H	5-Imidazolyl		Z
73	H	H	H	H	3-Pyridinyl		E
74^a	H	H	H	H	3-Pyridinyl		Z
77	H	-F	H	H	3-Pyridinyl		E
78^a	H	-F	H	H	3-Pyridinyl		Z
79^a	H	-Cl	H	H	3-Pyridinyl		E
80	H	-Cl	H	H	3-Pyridinyl		Z
81	H	-Br	H	H	3-Pyridinyl		E
82	H	-Br	H	H	3-Pyridinyl		Z
83^a	H	-OCH3	H	H	3-Pyridinyl		E
84^a	H	-OCH3	H	H	3-Pyridinyl		Z
86	-CH3	H	H	H	3-Pyridinyl		E
87	-F	H	H	H	3-Pyridinyl		E
88	-Cl	H	H	H	3-Pyridinyl		Z
89	-Cl	H	H	H	3-Pyridinyl		E
90	H	H	H	-OCH3	3-Pyridinyl		E
91	H	H	H	H	4-Pyridinyl		Z
93	H	-F	H	H	4-Pyridinyl		E
94	H	-F	H	H	4-Pyridinyl		Z
95	H	-Cl	H	H	4-Pyridinyl		E
96	H	-Cl	H	H	4-Pyridinyl		Z
97	H	-Br	H	H	4-Pyridinyl		E
98	H	-Br	H	H	4-Pyridinyl		Z
99	H	-OCH3	H	H	4-Pyridinyl		E
100	H	-OCH3	H	H	4-Pyridinyl		Z
103	H	H	-OCH3	H	4-Pyridinyl		E
104	H	H	-OCH3	H	4-Pyridinyl		Z
106^a	H	H	-CH3	H	4-Pyridinyl		E
107	H	H	-CH3	H	4-Pyridinyl		Z
H (Abiraterones)
	A		B		C		n
108	-OCH3		-F		-OH		1
109	-F		H		-OH		2
110	-F		-F		-OH		2
111	-OCH3		-F		-OH		2
113^a	-F		H		H		1
114^a	-OH		-OH		H		2
115	-OH		-F		H		2
116^a	-F		-H		-OH		1
120	-F		H		H		2
121	-F		F		H		2
I (Heteroarylindane/dihydronaphthalenes)
	A		B	Het		Het1		n
112	4-Fluoro-5-hydroxyphenyl		H	4-Pyridinyl				1
117^a	4-Fluorophenyl		H	4-Pyridinyl				1
118	4,5-Difluorophenyl		H	4-Pyridinyl				1
119	4,5-Dihydroxyphenyl		H	4-Pyridinyl				1
122	H		H			3-Pyridinyl		0
123	H		H			3-Pyridinyl		1
124	-OCH3		H			3-Pyridinyl		0
125	-OCH3		H			3-Pyridinyl		1
131	H		H			1-Imidazoyl		1
132	H		-OCH3			3-Pyridinyl		0

^aTest set members.

Table 2.  Observed and calculated CYP11B2 and CYP11B1 inhibitory activities and selectivity (CYP11B2/CYP11B1) of different classes of compounds.

Sl. no.	CYP11B2 inhibitory activity			CYP11B1 inhibitory activity		CYP11B2/CYP11B1 selectivity
	Obs^a	Cal^b	Cal^c	Obs^d	Cal^e	Obs^f	Cal^g	Cal^h
Training set
1	5.208	5.714	5.624	2.802	2.997	2.406	2.618	2.475
2	5.155	5.101	5.242	2.98	2.984	2.175	2.427	2.482
3	5.538	5.131	4.950	3.161	3.331	2.377	2.066	1.884
5	5.481	5.438	5.576	3.606	3.091	1.875	2.099	2.278
7	6.097	5.375	5.354	3.943	3.003	2.154	2.415	2.493
8	6.222	5.599	5.418	4.284	3.396	1.938	1.808	1.843
9	4.886	5.034	5.207	2.818	3.615	2.068	1.332	2.189
12	5.42	5.425	5.832	3.058	3.389	2.362	1.908	2.159
13	5.921	5.264	5.552	4	3.419	1.921	1.765	1.704
14	5.292	5.692	5.557	3.428	3.535	1.864	1.773	2.082
15	6.097	5.789	5.754	4.824	4.236	1.273	1.711	1.729
18	5.161	5.199	4.980	3.701	3.203	1.46	1.379	1.722
19	5.041	4.924	5.198	3.212	2.985	1.829	1.472	1.228
21	4.658	4.736	5.007	2.754	3.164	1.904	1.379	1.310
22	5.658	5.365	5.515	3.362	3.724	2.296	2.043	2.074
23	6.301	5.832	6.406	4.004	4.203	2.297	1.091	1.130
24	6.699	6.009	5.646	5	5.179	1.699	1.405	1.881
25	5.319	5.411	5.449	3.821	3.375	1.498	1.474	1.788
26	6.222	5.417	5.406	4.174	3.318	2.048	1.984	2.163
27	5.509	5.126	5.329	3.074	3.331	2.435	1.837	2.166
28	6.301	4.946	5.020	4.194	3.389	2.107	1.786	2.256
29	3.812	4.163	4.335	3.021	2.775	0.791	2.324	1.776
30	4.276	4.936	4.925	3.194	3.491	1.082	1.593	1.911
31	5.108	4.568	4.808	2.552	2.862	2.556	2.000	1.909
33	5.409	4.995	4.703	2.449	1.888	2.96	2.663	1.998
35	5.114	4.477	4.811	2.742	2.320	2.372	2.329	2.171
36	5.119	4.348	4.723	2.61	2.403	2.509	1.890	2.801
37	4.62	4.674	4.832	2.532	3.024	2.088	1.658	2.108
38	5.523	4.782	4.734	3.105	3.139	2.418	1.689	1.672
40	3.924	4.418	4.987	1.62	2.509	2.304	2.676	1.963
41	4.187	4.176	4.143	1.703	2.234	2.484	2.528	2.044
43	4.553	4.831	4.748	1.947	2.188	2.606	2.451	2.275
45	4.553	4.770	4.574	–	–	–	–	–
46	4.022	3.664	3.242	–	–	–	–	–
47	4.602	4.428	4.595	–	–	–	–	–
48	4.959	4.801	4.740	–	–	–	–	–
49	3.907	5.098	4.759	–	–	–	–	–
50	3.728	3.535	3.473	–	–	–	–	–
51	4.638	4.021	4.390	2.573	2.847	2.065	1.637	0.949
53	4.886	5.506	4.880	2.599	3.148	2.287	2.256	2.136
55	4.538	4.848	4.229	2.565	2.899	1.973	2.457	2.352
57	3.529	4.078	3.933	3.684	3.965	–0.155	0.339	0.259
58	4.921	4.258	4.177	3.094	2.674	1.827	1.692	1.348
59	4.606	4.276	4.445	4.503	3.887	0.103	0.089	–0.040
61	4.387	4.588	4.546	4.587	3.763	–0.2	0.287	0.029
62	4.959	4.740	4.581	5.215	4.916	–0.256	–0.412	–0.553
63	4.644	4.826	4.586	5.161	4.869	–0.517	–0.288	–0.111
64	4.445	4.738	4.538	4.824	3.736	–0.379	0.379	0.373
65	4.447	5.018	4.694	4.91	4.765	–0.463	–0.364	–0.101
68	4.857	3.992	4.166	4.952	5.097	–0.095	–0.470	–0.454
70	5.432	4.928	4.603	4.71	4.740	0.722	–0.554	–0.261
71	4.032	4.342	4.476	4.582	3.441	–0.55	0.111	0.185
72	4.987	4.617	4.621	4.629	4.622	0.358	–0.551	–0.270
73	4.959	4.744	4.542	3.052	3.031	1.907	1.737	1.362
75	4.658	4.204	4.297	3.146	3.230	1.512	1.593	1.290
76	3.851	4.233	4.096	2.846	3.763	1.005	1.162	1.120
77	5.155	4.049	4.507	3.507	3.277	1.648	1.624	1.435
80	4.137	4.451	4.087	3.569	3.345	0.568	1.127	1.353
81	4.432	4.182	4.275	2.713	2.853	1.719	1.588	1.674
82	3.767	4.107	4.102	3.495	3.217	0.272	1.292	1.347
85	4.244	4.784	5.014	3.044	3.081	1.2	2.105	1.766
86	3.967	4.410	4.077	3.117	3.115	0.85	1.953	1.662
87	4.678	4.224	4.499	3.111	3.278	1.567	1.652	1.617
88	5.046	5.471	4.552	3.517	2.963	1.529	1.633	1.684
89	4.509	5.101	4.575	3.182	3.358	1.327	1.174	1.332
90	4.569	4.770	4.411	3.02	3.601	1.549	1.509	1.115
91	4.745	4.744	4.665	3.031	3.645	1.714	1.173	1.025
93	4.824	5.140	5.674	2.959	3.255	1.865	1.656	1.644
94	4.538	4.264	4.669	4.469	3.857	0.069	1.041	1.131
95	4.745	5.357	5.373	2.82	2.929	1.925	1.628	1.645
96	4.444	4.741	4.435	3.521	3.470	0.923	1.007	1.283
97	4.62	5.043	5.381	2.578	2.825	2.042	1.613	1.643
98	4.252	4.428	4.399	3.315	3.340	0.937	0.993	1.278
99	4.229	5.152	5.090	–	–	–	–	–
100	4.26	4.550	4.485	–	–	–	–	–
101	4.658	5.158	5.334	–	–	–	–	–
103	5.523	5.789	5.719	–	–	–	–	–
104	4.585	4.975	4.813	–	–	–	–	–
107	5.097	4.395	4.403	–	–	–	–	–
108	3.361	3.567	3.396	3.536	2.836	–0.175	0.436	0.219
109	3.076	3.395	3.747	2.936	3.052	0.14	0.742	0.293
110	2.776	3.285	3.078	2.507	2.759	0.269	0.607	0.711
111	3.025	3.445	3.152	3.164	3.046	–0.139	0.375	0.516
112	3.004	3.389	3.518	2.561	2.937	0.443	1.076	0.976
115	3.231	3.328	3.486	2.863	3.009	0.368	0.926	0.443
118	3.507	3.379	3.656	–	–		–	–
119	2.826	3.445	3.464	–	–		–	–
120	3.286	3.746	4.311	–	–		–	–
121	3.246	3.297	3.598	–	–		–	–
122	4.886	4.504	4.634	2.621	2.798	2.265	1.965	1.966
123	5.155	4.784	4.651	2.762	3.032	2.393	1.837	1.812
124	5.398	4.896	4.753	2.245	2.731	3.153	2.674	3.041
125	5.669	5.580	5.453	3.238	2.917	2.431	2.495	2.471
126	5.155	4.618	4.420	2.897	3.115	2.258	1.502	1.282
127	4.523	4.277	4.427	2.674	3.287	1.849	1.367	1.316
129	4.886	4.492	4.613	2.889	3.194	1.997	1.719	1.814
130	3.754	4.078	4.062	2.792	3.372	0.962	1.457	1.772
131	3.476	5.166	5.075	3.194	4.563	0.282	0.897	0.820
132	4.347	5.154	4.937	–	–		–	–
Test set
4	5.678	5.350	5.318	3.238	2.917	2.44	2.426	2.456
6	5.347	5.022	4.879	3.336	3.345	2.011	1.813	1.849
10	4.027	4.425	4.432	2.049	3.158	1.978	1.889	1.316
11	5.377	5.720	6.092	3.623	3.439	1.754	2.132	2.194
16	5.678	5.251	5.660	3.593	3.009	2.085	2.009	2.014
17	2.915	4.438	3.986	1.423	2.902	1.492	0.824	0.839
20	6.699	5.510	5.238	4.509	3.286	2.19	1.768	2.022
32	5.569	4.635	4.827	2.709	2.145	2.86	2.818	1.688
34	4.959	4.635	4.851	2.364	2.756	2.595	1.719	2.225
39	5.301	4.631	4.683	3.134	3.193	2.167	1.266	2.354
42	4.523	4.184	4.588	2.016	2.418	2.507	2.932	1.800
44	4.553	4.967	4.886	–	–		–	–
52	4.824	4.668	4.753	2.532	2.906	2.292	1.903	1.708
54	4.481	5.384	5.024	2.349	3.059	2.132	2.190	2.087
56	4.721	4.812	4.502	4.092	4.262	0.629	1.197	1.236
60	5.018	4.811	4.612	5.481	4.966	–0.463	–0.491	–0.493
66	4.325	4.649	4.464	4.728	3.739	–0.403	–0.020	0.181
67	4.777	3.701	3.925	4.686	3.964	0.091	0.224	0.101
69	4.052	4.624	4.536	4.542	3.571	–0.49	0.166	0.201
74	4.036	4.560	4.366	4.06	3.518	–0.024	1.285	0.975
78	4.959	4.313	4.497	3.903	3.728	1.056	1.171	1.052
79	4.585	4.484	4.264	2.832	2.956	1.753	1.602	1.674
83	4.469	4.989	4.957	2.839	2.917	1.63	2.359	1.865
84	4.585	4.351	4.124	3.102	2.917	1.483	1.787	1.345
92	4.824	4.860	5.075	3.845	3.207	0.979	1.489	1.394
102	4.252	4.502	4.646	–	–	–	–	–
105	4.959	5.177	4.774	–	–	–	–	–
106	5.398	5.137	5.085	–	–	–	–	–
113	3.265	3.901	4.322	2.968	3.722	0.297	1.966	1.540
114	2.634	2.966	2.785	2.671	3.083	–0.037	0.735	–0.705
116	3.088	2.990	3.159	–	–		–	–
117	3.917	3.542	4.131	–	–		–	–
128	5.301	4.621	4.552	3.298	3.194	2.003	1.508	1.644

Note. Obs^a, observed CYP11B2 inhibitory activity (refs. 36–41, 43); Cal^b, calculated from Equation (1); Cal^c, calculated from Equation (2); Obs^d, observed CYP11B1 inhibitory activity (refs. 36–41, 43); Cal^e, calculated from Equation (3); Obs^f, observed selectivity (CYP11B2 vs. CYP11B1); Cal^g, calculated from Equation (4); Cal^h, calculated from Equation (5).

Figure 1.  Aligned geometry of the training set compounds.

Table 3.  K-means clustering of compounds using standardized descriptors.

Cluster no.	No. of compounds in cluster	Compounds (Sl. nos.) in each cluster
1	5	1	3	55	56	136
2	12	83	92	93	101	104	112	113	114	115	116	119	139
3	9	52	65	66	69	72	75	76	77	79
4	15	62	67	68	70	71	73	81	82	84	97	103	118
		135	138	144
5	9	5	13	25	29	125	132	140	141	142
6	16	6	8	45	74	78	80	85	86	88	98	99	100
		105	106	108	134
7	9	2	4	7	9	58	91	111	137	147
8	7	53	87	89	90	107	109	110
9	9	24	120	121	122	123	126	127	128	133
10	8	10	18	20	22	47	51	124	131
11	18	11	12	14	15	17	19	21	23	26	27	28	31
		46	49	50	117	129	130
12	15	30	32	33	34	35	36	37	38	39	40	41	42
		43	44	48

Table 4.  Comparative table of statistical qualities of different models

	Model	Variables	R^2	Q^2	R^2pred	r^2m (test)	r^2m (LOO)	r^2m (overall)
CYP11B2 modeling
GFA	M1	Jurs_TPSA, Jurs_FNSA_3, ShapeRMS, RadOfGyration, Jurs_RASA, Jurs_WPSA_2	0.599	0.543	0.641	0.559	0.385	0.432
GFA spline	M2	<Jurs_TPSA-55.2527>, <2.4853-AlogP98>, <LUMO-1.68653>, <ShapeRMS-0.655548>, <COSV-163.577>, Density	0.672	0.630	0.611	0.569	0.472	0.447
G/PLS	M3 Eq. (1)	ShapeRMS, Hbondacceptor, Jurs_TPSA, RadOfGyration, Sr, Shadow_XYfrac, PMI_mag	0.619	0.550	0.536	0.529	0.528	0.527^a
G/PLS spline	M4 Eq. (2)	<1.33555-Sr>, <88.2511-Shadow_XY>, <Shadow_XYfrac-0.651254>, <4.18953-Jurs_RNCS>, <Jurs_TPSA-70.8915>, ShapeRMS, AlogP98	0.614	0.543	0.583	0.565	0.522	0.554^a
CYP11B1 modeling
GFA	M5	Jurs_WNSA_2, Jurs_RNCS, Shadow_XYfrac, Jurs_DPSA_2, Jurs_RPCG, Jurs_SASA	0.620	0.519	0.502	0.479	0.390	0.409
GFA spline	M6	<Shadow_Ylength-9.01347>, Jurs_RNCS, <COSV-167.814>, <14.47-Shadow_Xlength>	0.641	0.598	0.543	0.511	0.440	0.454
G/PLS	M7	Jurs_RPCG, Jurs_RNCS, ShapeRMS, Shadow_XYfrac, Jurs_WPSA_1, Jurs_WNSA_2, Shadow_nu	0.595	0.514	0.510	0.496	0.489	0.498
G/PLS spline	M8 Eq. (3)	<4.04134- Jurs_RNCS>, <Shadow_YZ-41.056>, <3.51287-RadOfGyration>, <COSV-167.814>, Jurs_RNCG, <-9.59302-Jurs_WNSA_3>	0.645	0.571	0.548	0.488	0.539	0.558^a
Selectivity modeling
GFA	M9	ShapeRMS, Jurs_RNCS, PMI_mag, Jurs_RPCS, Shadow_XY	0.609	0.545	0.643	0.560	0.521	0.529
GFA spline	M10 Eq. (4)	Jurs_RNCS, <Shadow_Ylength-9.08574>, <1-Hbonddonor>, <4.12361-RadOfGyration>, Jurs_SASA	0.708	0.659	0.653	0.618	0.578	0.588^a
G/PLS	M11	Chiral centers, Jurs_RNCS, Jurs_RPCS, Rotatablebonds, Shadow_nu, Jurs_TPSA, COSV	0.634	0.557	0.734	0.653	0.332	0.452
G/PLS spline	M12 Eq. (5)	<7.40455-Shadow_Ylength>, <LUMO-2.06415>, <6.0479-Jurs_RNCS>, <Jurs_WNSA_2 + 139.393>, Hbonddonor, <Jurs_SASA-584.135>, <4.12361-RadOfGyration>	0.709	0.634	0.718	0.702	0.604	0.633^a

^aOnly models with r_m²_(overall) values more than 0.5 (Equations (1)–(5)) have been discussed in detail in the text.

Pinto-Bazurco Mendieta MA, Negri M, Jagusch C, Müller-Vieira U, Lauterbach T, Hartmann WR. Synthesis, biological evaluation, and molecular modeling of abiraterone analogues: novel CYP17 inhibitors for the treatment of prostate cancer. J Med Chem 2008; 1:5009–18.

 Google Scholar