Descriptor analysis of estrogen receptor β-selective ligands using 2-phenylquinoline, tetrahydrofluorenone and 3-hydroxy 6H-benzo[c]chromen-6-one scaffolds

Figures & data

Table 1.  Structural features, observed and predicted ERβ IC₅₀ values and ERα/β fold selectivity for 2-phenylquinoline scaffold.

S. No	R^1	R^2	R^3	R^4	ERβ IC50 (nM)		ERα/β
					Observed	Predicted	Observed	Predicted
1	H	H	H	H	2.232	2.220	1.000	1.017*
2	H	H	Cl	H	1.477	1.765*	1.322	#
3	H	H	Br	H	1.944	2.051	1.113	1.370
4	H	H	H	Cl	0.662	1.129*	1.662	1.712
5	F	H	H	Cl	0.724	0.743	1.662	1.387*
6	H	H	H	Br	0.633	0.888*	1.698	1.630
7	F	H	H	Br	0.531	0.503	1.919	1.634
8	F	F	H	Br	1.556	1.364	1.342	1.325
9	H	H	H	CH=CH2	1.778	1.650*	0.903	0.697*
10	F	H	H	CH=CH2	1.643	1.915	0.954	1.105
11	H	H	H	C2H5	1.716	#	1.079	1.192
12	F	H	H	C2H5	1.897	1.632	1.342	0.836*
13	H	H	H	C≡CH	1.875	2.060*	1.301	1.011
14	F	H	H	C≡CH	1.431	1.938	1.681	0.957*
15	F	F	H	C≡CH	2.875	2.266	0.778	0.795
16	H	H	H	CN	1.447	1.526	1.204	#
17	F	H	H	CN	1.361	1.579*	1.662	1.491
18	H	H	H	COCH3	2.344	2.365	1.146	0.994*
19	F	H	H	COCH3	1.968	2.067	1.556	1.338
20	F	H	H	C6H5	2.324	#	1.278	1.421
21	H	H	H	OCH3	3.075	2.260*	0.778	0.403*

*Compounds used in the test set.

#Outlier.

Table 2.  Structural features, observed and predicted ERβ IC₅₀ values and ERα/β fold selectivity for tetrahydrofluorenone scaffold.

S. No	R^1	R^2	ERβ IC50 (nM)		ERα/β
			Observed	Predicted	Observed	Predicted
1	H	H	3.186	3.164	0.845	0.884
2	CH3	H	2.971	2.998	0.698	0.652*
3	C2H5	H	2.572	2.846	1.431	#
4	CH3CH2CH2	H	2.338	2.694	1.079	1.195
5	CH3CH2CH2CH2	H	2.274	2.544*	1.531	#
6	CH3CH2CH2CH2 CH2	H	2.975	2.390	0.602	0.557
7	C6H5CH2	H	3.625	2.381*	0.301	0.625*
8	CH3	CH3	1.799	1.520*	1.278	1.477
9	C2H5	CH3	1.447	1.366	1.633	1.416
10	CH3CH2CH2	CH3	1.041	1.237	1.414	1.417*
11	Iso-propyl	CH3	2.089	#	1.079	0.641*
12	CH3CH2CH2CH2	CH3	1.204	1.063	1.591	1.417
13	Iso-butyl	CH3	1.301	1.099	1.000	#
14	C6H5	CH3	1.176	1.076*	1.505	1.485
15	CH3	Br	1.127	0.877	1.819	1.785
16	C2H5	Br	0.653	0.725	1.851	1.723
17	CH3CH2CH2	Br	0.643	0.576*	1.255	1.724*
18	CH3CH2CH2CH2	Br	0.255	0.421	1.880	1.738
19	CH3CH2CH2CH2	Et	1.113	0.521*	1.301	1.419*
20	CH3CH2CH2CH2	Pr	0.176	0.369	1.301	1.418
21	CH3CH2CH2CH2	Bu	1.176	0.294*	1.255	1.383
22	CH3CH2CH2CH2	2-furyl	0.491	1.024	1.799	1.352*
23	CH3CH2CH2CH2	2-thienyl	0.204	0.179	1.653	1.494
24	CH3CH2CH2CH2	Phenyl	0.079	0.548*	1.531	1.364
25	CH3CH2CH2CH2	CN	1.579	1.397	1.633	1.419*
26	CH3CH2CH2CH2	CF3	0.176	−1.822*	1.929	1.965
27	CH3CH2CH2CH2	Cl	0.724	0.722	1.342	1.544
28	CH3CH2CH2CH2	I	0.113	−0.007*	1.977	1.884*
29	C6H5	Br	0.397	0.410	1.653	1.788
30	C6H5	2-furyl	1.204	0.977	1.380	1.487
31	C6H5	CN	1.505	1.386	1.477	1.468*

*Compounds used in the test set.

#Outlier.

Table 3.  Structural features, observed and predicted values for ERβ IC₅₀ values and ERα/β fold selectivity for 3-hydroxy- 6H-benzo[c]chromen-6-one scaffold.

S. No.	R^1	R^2	R^3	R^4	R^5	ERβ IC50 (nM)		ERα/β
						Observed	Predicted	Observed	Predicted
1	CH3	CH3	H	H	H	1.968	2.326*	2.029	1.560
2	CH3	H	OCH3	H	H	2.488	2.634	1.505	0.966*
3	CH3	H	Br	H	H	2.107	2.826	1.892	1.594
4	CH3	H	H	H	H	3.161	2.363*	0.845	0.965
5	CH3	H	CH=CH2	H	H	2.491	2.047	1.176	1.556*
6	H	H	CH3	H	CH3	1.954	2.106	0.812	#
7	C2H5	H	Br	H	H	3.369	#	0.361	0.553
8	CH3	H	H	H	CH3	2.513	2.137	1.477	1.601*
9	CH3	H	H	H	CH=CH2	2.318	2.044*	1.681	1.608
10	CH3	H	H	H	Propenyl	2.064	1.424	1.414	#
11	CH3	CH3	OCH3	H	H	2.068	2.164*	1.929	1.004*
12	CH3	CH3	NH2	H	H	2.445	2.591	1.707	1.573
13	CH3	CH3	NHSO2CH3	H	H	2.636	2.696*	0.991	1.621
14	CH3	Br	H	Br	H	1.380	1.494	1.397	1.553
15	CH3	CH3	H	H	CH3	1.903	1.761	1.579	1.837
16	CH3	CH3	NHCHO	H	H	2.980	2.533	1.000	1.025*
17	CH3	H	Br	CH3	H	2.332	2.204	1.505	1.549
18	CH3	H	OCH3	Br	H	1.886	1.874	2.110	#
19	CH3	H	Br	Butenyl	H	1.414	1.234	1.623	1.744*
20	CH3	H	CH3	H	CH3	1.301	1.550*	2.264	2.367
21	CH3	H	CH3	H	Br	1.643	1.653	1.851	1.427
22	CH3	H	CH3	H	H2C=CH-CH2	1.544	1.159*	2.454	2.395
23	CH3	H	CH3	H	CH=CH2	1.000	1.405	3.000	2.716*
24	CH3	H	OCH3	H	CH3CH2	1.838	1.691*	2.152	1.916
25	CH3	H	OCH3	H	CH=CH2	1.724	1.923	2.274	2.458
26	CH3	H	CH3	Br	CH3	1.755	1.444*	2.243	2.133*
27	CH3	H	CH3	OCH3	CH3	1.204	1.053	2.411	2.411
28	CH3	Br	CH3	OCH3	CH3	0.060	0.680	2.176	2.185*

*Compounds used in the test set.

#Outlier.

Table 4.  Molecular descriptors selected for the study.

Descriptors	Class of descriptor
Molecular weight	Structural
Number of atoms	Structural
Number of halogen atoms	Structural
Number of heteroatoms	Structural
Number of hydrogen bond donors	Structural
Number of hydrogen bond acceptors	Structural
Ellipsoidal volume	Spatial
Verloop L, B1-B5	Steric
Kappa indices (α1–3)	Shape
Lipophilicity	Thermodynamic
Electrotopological state indices	Electronic

Table 5.  Physicochemical descriptors that significantly influenced the 2-phenylquinoline derivatives binding at ER receptors.

S. No.	Log P	Number of heteroatoms at R^4	Ellipsoidal volume (whole molecule)	Kappa 2 index of substituents at R^2
1	3.650	0	963.503	0.0
2	4.168	0	883.183	0.0
3	3.842	0	1307.560	0.0
4	4.168	1	576.104	0.0
5	4.608	1	593.980	0.0
6	4.442	1	750.821	0.0
7	4.882	1	742.811	0.0
8	3.901	1	836.976	0.5
9	4.299	0	1284.100	0.0
10	3.998	0	1874.880	0.0
11	4.216	0	1689.270	0.0
12	4.321	0	1324.970	0.0
13	3.832	0	2075.810	0.0
14	3.971	0	1386.10	0.0
15	3.598	0	1971.28	0.5
16	3.715	1	986.599	0.0
17	3.655	1	1049.600	0.0
18	2.759	1	1287.69	0.0
19	3.098	1	1376.590	0.0
20	5.174	0	1199.310	0.0
21	2.879	1	1577.20	0.0

Figure 1.  Skeletal structure of estrogenic compounds. The moieties derivatised in each compound is indicated and referred in the Tables 1, 2, and 3.

Table 6.  QSAR statistics of the best multiple linear regression equations.

Data set	n	R^2	R	S.D.	Q	q^2	F value	RMSE		Randomized		R^2 pred
								Training set	Test set	R^2	S.D.
2-phenylquinoline ERβ IC50	12	0.822	0.906	0.305	2.970	0.720	20.849	0.264	0.395	0.131	0.785	0.853
2-phenylquinoline ERα/β	12	0.724	0.850	0.217	3.917	0.579	19.048	0.173	0.226	0.192	0.621	0.548
Tetrahydrofluorenone ERβ IC50	20	0.934	0.966	0.270	3.577	0.758	75.970	0.245	0.707	0.174	0.537	0.652
Tetrahydrofluorenone ERα/β	18	0.850	0.921	0.147	6.265	0.717	42.700	0.134	0.278	0.101	0.724	0.667
3-hydroxy 6H-benzo[c] chromen-6-one ERβ IC50	18	0.723	0.850	0.385	2.207	0.556	19.671	0.351	0.338	0.142	0.697	0.612
3-hydroxy 6H-benzo[c] chromen-6-one ERα/β	16	0.780	0.883	0.310	2.848	0.602	14.194	0.268	0.373	0.157	0.954	0.625

Figure 2.  Plot of predicted vs. observed values of ERβ binding affinity and fold selectivity of the ligands against ER receptors. (A), (C) and (E) represent the ERβ binding affinity of phenylquinoline, tetrahydrofluorenone and 3-hydroxy 6H-benzo[c]chromen-6-one ligands respectively. (B), (D) and (F) represent the ERβ fold selectivity of phenylquinoline, tetrahydrofluorenone and 3-hydroxy 6H-benzo[c]chromen-6-one ligands, respectively.

Figure 3.  (A) Docked pose of most active compound 7 (green) and least active compound 21 (grey) in the phenylquinoline series with ERβ. Only key residues (pink), of the ERβ binding site are shown for simplicity. (B) Docked pose of most active compound 28 (green) and least active compound 7 (grey) in the tetrahydrofluorenone series with ERβ. Only key residues (pink), of the ERβ binding site are shown for simplicity. (C) Docked pose of most active compound 23 (green) and least active compound 7 (grey) in the tetrahydrofluorenone series with ERβ. Only key residues (pink), of the ERβ binding site are shown for simplicity.

Table 7.  Physicochemical descriptors that significantly influenced the tetrahydrofluorenone derivatives binding at ER receptors.

S. No.	Verloop B2 of R^2	Lipophilicity	Number of halogen atoms at R^2	Verloop B1 of R^2	Verloop B2 of R^1
1	1.000	1.653	0	1.000	1.000
2	1.000	2.086	0	1.000	1.800
3	1.000	2.483	0	1.000	1.889
4	1.000	2.879	0	1.000	1.835
5	1.000	3.275	0	1.000	1.898
6	1.000	3.672	0	1.000	2.120
7	1.000	3.700	0	1.000	1.892
8	1.702	2.364	0	1.650	1.696
9	1.703	2.761	0	1.650	1.902
10	1.691	3.157	0	1.650	1.903
11	1.701	3.091	0	1.650	2.659
12	1.702	3.553	0	1.650	1.899
13	1.697	3.487	0	1.650	1.899
14	1.691	3.581	0	1.650	1.666
15	1.900	2.262	1	1.900	1.689
16	1.900	2.658	1	1.900	1.900
17	1.900	3.055	1	1.900	1.897
18	1.900	3.451	1	1.900	1.849
19	1.903	3.949	0	1.650	1.895
20	1.902	4.346	0	1.650	1.896
21	1.864	4.742	0	1.650	2.018
22	1.690	3.719	0	1.650	2.124
23	2.055	4.062	0	1.713	1.903
24	1.728	4.770	0	1.650	2.080
25	1.650	2.951	0	1.650	1.896
26	2.646	3.969	3	2.168	2.195
27	1.800	3.177	1	1.800	2.093
28	2.030	3.917	1	2.030	1.892
29	1.900	3.479	1	1.900	1.677
30	1.708	3.747	0	1.650	1.661
31	1.650	2.979	0	1.650	1.725

Table 8.  Physicochemical descriptors that significantly influenced the 3-hydroxy 6H-benzo[c]chromen-6-one derivatives binding at ER receptors.

S. No.	Molecular surface area (whole molecule)	Number of heteroatoms at R^3	Verloop B2 of R^1	Verloop B3 of R^5	κAlpha 3 index at R^4
1	218.480	0	1.697	1.000	0.000
2	227.157	1	1.815	1.000	0.000
3	219.649	1	1.690	1.000	0.000
4	218.036	0	1.815	1.000	0.000
5	227.817	0	1.698	1.000	0.000
6	225.502	0	1.000	1.902	0.000
7	245.908	1	1.897	1.000	0.000
8	224.297	0	1.808	1.895	0.000
9	235.489	0	1.805	1.880	0.000
10	252.072	0	1.716	1.925	0.000
11	248.048	1	1.808	1.000	0.000
12	228.816	1	1.694	1.000	0.000
13	279.919	4	1.685	1.000	0.000
14	249.354	0	1.698	1.000	0.000
15	238.977	0	1.810	2.056	0.000
16	253.295	2	1.804	1.000	0.000
17	243.910	1	1.699	1.000	0.000
18	256.760	1	1.703	1.000	0.000
19	281.690	1	1.816	1.000	3.351
20	239.776	0	1.688	2.034	0.000
21	243.152	0	1.804	1.600	0.000
22	267.061	0	1.695	2.228	0.000
23	252.842	0	1.683	1.868	0.000
24	266.523	1	1.789	2.220	0.000
25	254.838	1	1.689	2.279	0.000
26	259.945	0	1.703	1.897	0.000
27	266.543	0	1.810	1.966	1.649
28	281.078	0	1.791	1.903	1.649