QSAR studies for the inhibition of the transmembrane carbonic anhydrase isozyme XIV with sulfonamides using PRECLAV software

Figures & data

Table I.  Structural details of sulfonamides/sulfamates used in the present study.

Table II.  PRECLAV descriptors used in the significant models.

Compd. no.	ray	pca	qgf	lhb	pon	lhf	raz	nss
1	1.2824	41.841	2.6591	9.937	0.5399	0.1006	1.423	2.8632
2	1.0703	41.841	2.6591	9.931	0.5401	0.1007	1.4086	2.8635
3	1.4718	41.841	2.6591	9.841	0.6228	0.1016	1.405	2.8763
4	1.5874	45.138	5.1481	9.569	0.8518	0.1045	1.545	2.8673
5	1.5224	37.884	2.4272	9.58	0.5978	0.1044	1.6681	2.8745
6	1.4973	34.868	2.2506	9.617	0.582	0.104	1.7877	2.8761
7	1.8039	28.696	1.8869	9.635	0.578	0.1038	2.0582	2.8764
8	2.0144	24.172	1.6233	9.656	0.579	0.1036	2.2465	2.8767
9	1.8595	26.329	2.8516	10.066	0.6534	0.0993	2.1076	2.8731
10	1.6011	25.218	3.1626	9.724	0.5358	0.1028	2.0372	2.8623
11	1.4879	18.548	2.3798	10.468	0.8406	0.0955	1.6309	0.3799
12	2.1487	28.646	1.57	8.608	1.4195	0.1162	2.3609	0.6642
13	1.8718	36.509	2.0398	8.408	0.912	0.1189	1.9781	0.6408
14	1.6063	44.902	2.8662	9.654	0.7215	0.1036	1.6641	2.8673
15	1.6305	47.739	2.6798	9.611	0.9454	0.104	1.6945	2.8673
16	1.7993	41.782	2.6825	9.623	0.8601	0.1039	1.8709	2.8623
17	1.6197	38.485	4.7176	9.664	0.8289	0.1035	1.6736	2.8731
18	1.5679	47.972	4.8034	9.553	0.8767	0.1047	1.6198	2.8679
19	1.5065	13.328	2.5485	10.052	0.0641	0.0995	1.6195	0.6418
20	2.7002	45.728	1.6634	9.552	2.1254	0.1047	2.7193	2.8675
21	2.2726	45.266	1.7973	8.939	1.511	0.1119	2.2406	2.873
22	1.9678	21.614	2.2638	9.901	1.3758	0.101	1.921	0.6508
23	1.9392	21.614	2.2638	9.753	1.2638	0.1025	2.0261	0.5729
24	2.1419	41.841	1.8421	8.44	1.8195	0.1185	2.2176	0.6329
25	1.4156	23.613	2.9754	9.703	0.7054	0.1031	2.2148	2.8619
26	1.4374	37.015	1.5074	8.442	1.336	0.1185	1.9521	1.0666
27	2.2049	37.379	1.3018	8.939	1.7383	0.1119	2.3458	0.4052
28	1.9996	35.99	0.3224	8.988	1.4455	0.1113	2.1721	0.5377
29	1.0322	38.081	1.5443	10.229	0.9975	0.0978	1.6977	2.8208
30	1.0221	45.269	2.1953	9.268	0.9268	0.1079	1.7484	2.8255

ray = Gyration radius Y of molecular area; pca = Percent of carbon; qgf = QSPR of mass fragment percents; lhb = E(lumo) - E(homo-1) gap; pon = RMS of distance to geometric center(H and Halogen atom); lhf = 1/[E(lumo) - E(homo-1)] ratio; raz = Gyration radius Z of molecular area; nss = minimum net charge of S atom.

Table III.  Quantum and Chemical descriptors computed by HyperChem used in the present study.

Compd. no.	MPC	LNC	MNC	SPC	SNC	SAC	EHOMO	ELUMO	χ	η	S	ω
1	2.879	0.03	0.957	4.572	4.571	9.143	− 210.1	− 9.76	100.21	− 109.9	− 0.009	− 45.66
2	2.863	0.066	0.952	4.332	4.332	8.664	− 207.1	− 8.1	99.5	− 107.6	− 0.009	− 46
3	2.877	0.237	0.953	4.576	4.576	9.154	− 211.1	− 7.52	101.82	− 109.3	− 0.009	− 47.4
4	2.867	0.02	0.953	4.415	4.418	8.833	− 229	− 4.05	112.52	− 116.5	− 0.009	− 54.3
5	2.875	0.003	0.953	4.42	4.419	8.839	− 211.9	− 3.3	104.33	− 107.6	− 0.009	− 50.56
6	2.864	0.004	0.954	4.324	4.331	8.655	− 228.8	− 17.78	105.54	− 123.5	− 0.008	− 45.16
7	2.877	0.29	0.953	4.649	4.648	9.297	− 212.1	− 11.01	100.57	− 111.5	− 0.009	− 45.32
8	2.877	0.247	0.953	4.737	4.754	9.491	− 213	− 10.75	101.14	− 111.8	− 0.009	− 45.74
9	2.865	0.151	0.959	8.476	8.477	16.953	− 227.3	− 29.6	98.69	− 128.4	− 0.008	− 37.9
10	2.881	0.045	0.32	8.126	8.124	16.25	− 224.6	− 22.21	101.24	− 123.4	− 0.008	− 41.51
11	0.306	0.045	0.299	1.44	1.439	2.879	− 208.1	− 26.54	90.78	− 117.3	− 0.009	− 35.12
12	2.904	0.109	1.17	8.651	8.651	17.302	− 224.1	− 23.99	100.07	− 124	− 0.008	− 40.36
13	2.884	0.017	0.996	4.812	4.813	9.625	− 214.8	− 29.81	92.53	− 122.3	− 0.008	− 34.99
14	2.867	0.017	0.953	4.332	4.331	8.663	− 232.9	− 13.35	109.77	− 123.1	− 0.008	− 48.93
15	2.868	0.007	0.954	4.497	4.497	8.994	− 235.2	− 14.84	110.18	− 125	− 0.008	− 48.55
16	2.863	0.038	0.954	4.599	4.599	9.198	− 241.6	− 29.87	105.86	− 135.7	− 0.007	− 41.28
17	2.873	0.206	0.954	4.576	4.576	9.152	− 216.8	− 4.08	106.37	− 110.4	− 0.009	− 51.22
18	2.868	0.015	0.953	4.736	4.736	9.472	− 230.1	− 13.82	108.17	− 121.9	− 0.008	− 47.95
19	2.903	0.0124	0.949	4.567	4.567	9.134	− 223.3	− 29.35	97	− 126.3	− 0.008	− 37.23
20	2.867	0.013	0.954	8.664	8.665	17.329	− 213.9	− 15.93	98.9	− 114.9	− 0.009	− 42.62
21	2.873	0.21	0.954	5.552	5.552	11.104	− 209.8	− 17.04	96.38	− 113.4	− 0.009	− 40.94
22	2.899	0.162	1.129	5.062	5.062	10.124	− 230.1	− 37.9	96.09	− 134	− 0.007	− 34.45
23	2.889	0.012	1.026	4.875	4.873	9.748	− 220.6	− 27.86	96.37	− 124.2	− 0.008	− 37.37
24	2.885	0.016	1	5.028	5.027	10.055	− 212.3	− 19.96	96.18	− 116.1	− 0.009	− 39.82
25	2.867	0.115	0.954	7.369	7.369	14.738	− 240.7	− 33.85	103.4	− 137.3	− 0.007	− 38.97
26	2.901	0.048	1.174	8.862	8.862	17.724	− 224.2	− 37.74	93.21	− 130.9	− 0.008	− 33.18
27	2.902	0.003	1.232	10.197	10.197	20.394	− 223.8	− 37.27	93.28	− 130.5	− 0.008	− 33.32
28	2.967	0.013	1.833	9.25	9.25	18.501	− 234.5	− 35.16	99.65	− 134.8	− 0.007	− 36.83
29	2.312	0.004	0.906	4.973	4.973	9.946	− 202.7	− 4.19	99.24	− 103.4	− 0.008	− 47.61
30	2.824	0.007	0.953	4.302	4.299	8.601	− 228.9	− 20.11	104.42	− 124.5	− 0.008	− 43.78
Compd. no.	DMt	DMx	DMY	DMz	Hf	SA	VOL	Ref	Pol.	log p	HE
1	4.879	3.676	0.187	3.203	− 53.08	257.04	496.95	44.1	14.27	0.15	− 11.33
2	4.605	3.384	1.597	2.684	− 48.72	271.97	490.52	47.76	14.27	0.15	− 13.02
3	6.239	4.664	3.132	3.03	− 51.64	267.69	489.21	44.1	14.27	0.15	− 11.39
4	4.723	2.672	2.871	2.632	− 49.75	304.64	541.71	51.92	16.11	0.05	− 11.66
5	5.666	3.024	3.861	2.838	− 95.64	280.64	498.19	48.39	14.18	0.29	− 12.48
6	4.619	2.914	19.65	2.998	− 55.1	334.69	579.76	52.68	18.04	0.57	− 10.93
7	6.311	3.622	3.99	3.285	− 46.35	311.5	545.77	55.8	16.9	0.01	− 12.13
8	6.358	3.713	3.883	− 3.401	− 34.64	308.26	554.13	52.65	20.36	1.41	− 10.73
9	7.822	2.11	4.361	6.141	− 270	359.22	696.31	63.42	18.33	− 0.08	− 16.04
10	5.243	0.97	5.108	− 0.677	− 128	367.33	673	63.25	18.69	3.42	− 17.47
11	1.258	− 1.167	− 0.349	− 0.313	− 95.91	272	485.22	39.14	15.27	0.2	− 12.12
12	7.995	5.159	− 6.065	− 0.721	− 49.83	462.72	840.15	79.01	25.07	3.24	− 24.39
13	4.486	2.346	− 2.423	− 2.958	− 62.67	312.8	568.39	55.5	18.56	2.78	− 17.95
14	5.812	4.223	1.229	3.799	− 98.04	337.04	551.07	46.22	15.4	0.4	− 13.62
15	5.739	1.727	2.344	4.945	− 106	362.18	612.26	53.21	18.14	0.98	− 23.84
16	4.129	1.206	0.167	3.945	− 135	340.66	558.1	43.16	15.48	3.43	− 14.67
17	5.554	1.975	2.848	4.34	− 23.9	316.06	547.8	49.18	15.63	0.25	− 19.43
18	4.501	3.25	0.33	− 3.094	− 57.13	340.43	595.97	53.63	17.94	4.17	− 11.95
19	5.497	− 4.285	2.844	1.941	− 16	263.03	440.13	38.34	12.38	0.62	− 21.39
20	4.911	3.321	− 2.597	1.298	− 97.9	479.42	923.3	90.52	30.09	1.28	− 19.24
21	5.843	3.471	3.726	2.865	13.4	357.47	715	70.48	23.87	4.98	− 18.75
22	3.325	− 6.432	− 1.456	− 2.957	− 50.8	345.52	549	47.78	16.78	0.44	− 16.33
23	4.104	− 1.489	2.125	− 3.18	− 31.5	319.86	542.75	47.78	16.13	0.78	− 13.14
24	5.237	3.298	− 2.754	− 2.994	− 62.32	412.2	702.05	65.02	22.22	3.16	− 13.62
25	7.238	0.794	1.406	− 7.056	− 123.26	388.02	646.97	62.35	19.27	0.85	− 12.19
26	4.863	− 1.387	− 3.065	− 3.512	− 119.9	461.52	804.1	77	25.17	− 0.04	− 9.62
27	5.788	− 5.033	− 2.223	1.799	− 164.5	569.72	977.01	91.82	30.83	− 0.75	− 10.98
28	1.849	1.321	− 0.79	− 1.026	− 47.33	408.42	739.69	80.13	23.18	6.56	− 18.33
29	6.321	4.136	− 1.048	4.664	− 329.4	421.91	731.02	64.03	22.83	− 0.36	− 8.9
30	3.217	3.102	− 0.281	0.806	− 11.5	274.74	561.29	56.01	17.39	2.517	− 10.99

MPC-Most positive charges; LNC-Least negative charges; MNC-Most Negative charges; SPC-Sum of positive charges; SNC-Sum of negative charges; SAC-Sum of absolute charges; E_HOMO(Kcal∖mol)-Highest occupied molecular orbital energy; E_LUMO, Kcal∖mol-Lowest unoccupied molecular orbital energy; χ,Kcal∖mol Electronegativity (χ = − 0.5(E_HOMO − E_LUMO)); η,Kcal∖mol Hardness (η = 0.5 (E_HOMO+ E_LUMO)); S-Mol∖Kcal, Softness (S = 1∖η); Pol(A³)Kcal∖mol-Electrophilicity (ω = χ²/2η); DM_tDebyes-Total molecular Dipole moment; DM_xDebyes-Molecular dipole moment at x-direction; DM_yDebyes-Molecular dipole moment at y-direction; DM_zDebyes-Molecular dipole moment at z-direction; H_fKcal∖mol-Heat of formation; SA(A²)-Surface area; V(A³)-Volume; Ref(A³)-Ref: refractivity; log P-The log of octanol-water partition coefficient; HE Kcal∖mol-Hydration energy.

Table IV.  Statically significant models for the set of 28 compounds using PRECLAV parameters.

Model	Parameters used	R^2	R^2A	Se	F
1	raz,nss	0.8732	0.8460	0.3162	89.4955
2	pca,pon,lhb	0.9096	0.8891	0.2670	83.8137
3	pca,ray,pon,lhf	0.9259	0.8985	0.2416	75.0196

Table V.  Statically significant models for the set of 28 compounds using HyperChem descriptors.

Model	Parameters Number used	R^2	R^2A	Se	F
1	ω	0.4906	0.4710	0.2669	25.036
2	POL, ω	0.6383	0.6094	0.2294	22.059
3	SA, HF, ω	0.7095	0.6732	0.2098	19.540
4	SA, Hf, χ, DMy	0.7598	0.7181	0.1949	18.192
5	SA, Hf, ω, SPC, SNC	0.8453	0.8101	0.1599	24.042
6	SA, Hf, ω, SPC, SNC, DMy	0.8698	0.8326	0.1502	23.382
7	SA, Hf, ω, SPC SNC, DMy, DMx	0.8840	0.8434	0.1452	21.780

Table VI.  Observed and estimated values of log hCAXIV their residue(for 28 compound's) using 4-varible models obtained using PRECLAV and HyperChem parameters.

		log hCAXIV
		PRECLAVE		HyperChem
Compd. no.	obs.	Est.	Res.	Est.	Res.
1	3.813	3.742	0.071	3.224	0.589
2	3.681	3.831	− 0.149	2.906	0.775
3	3.732	3.53	0.203	3.071	0.662
4	3.505	3.312	0.193	3.753	− 0.248
5	2.255	3.113	− 0.858	–	–
6	1.322	–	–	1.706	− 0.384
7	1.176	–	–	–	–
8	1.898	2.157	− 0.259	2.509	− 0.612
9	2.833	2.576	0.256	3.002	− 0.17
10	2.756	2.488	0.268	2.39	0.365
11	2.389	2.397	− 0.007	2.466	− 0.077
12	1.114	0.916	0.197	1.806	− 0.692
13	1.681	1.702	− 0.021	2.242	− 0.561
14	3.584	3.445	0.139	3.57	0.015
15	3.513	3.407	0.105	3.35	0.163
16	2.892	3.053	− 0.161	3.434	− 0.542
17	3.161	2.991	0.17	2.946	0.215
18	3.462	3.455	0.008	3.242	0.22
19	2.447	2.401	0.046	2.498	− 0.051
20	1.881	1.886	− 0.005	1.557	0.324
21	1.949	2.041	− 0.092	1.394	0.556
22	1.613	1.605	0.008	2.158	− 0.545
23	1.633	1.604	0.029	2.066	− 0.432
24	1.398	1.243	0.155	1.725	− 0.327
25	2.389	2.333	0.056	2.64	− 0.251
26	1.431	1.638	− 0.207	1.328	0.104
27	1.38	1.443	− 0.062	0.548	0.832
28	1.519	1.71	− 0.192	1.871	− 0.353
29	3.164	3.476	− 0.312	3.176	− 0.012
30	3.72	3.298	0.422	3.281	0.439

Table VII.  VIF values, Tolerance, Eigenvalue and Condition Number for the descriptors contained in the proposed models using PRECLAV descriptors for the set of 28 compounds.

Model	Variables Used	Variance Inflation factor	R-Squared	Tolerance	Eigenvalue	Condition Number
1	nss	1.0826	0.0763	0.9237	1.276186	1.00
	raz	1.0826	0.0763	0.9237	0.723814	1.76
2	pca	1.1242	0.1105	0.8895	1.782082	1.00
	Pon	1.4900	0.3289	0.6711	0.784004	2.27
	lhb	1.5270	0.3451	0.6549	0.433915	4.11
3	pca	1.2600	0.2063	0.7937	2.196745	1.00
	pon	2.6287	0.6196	0.3804	1.050654	2.09
	lhf	1.5196	0.3420	0.6580	0.518117	4.24
	Ray	2.1934	0.5441	0.4559	0.234484	9.37

Since all VIF's are less than 10, multicollinearity is not a problem. All Condition Numbers less than 100. Multicollinearity is NOT a problem.

Table VIII.  VIF values, Tolerance, Eigenvalue and Condition Number for the best four - variable model for the set of 28 compounds using HyperChem parameters.

Independent Variable	Variance Inflation factor	R-Squared	Tolerance	Eigenvalue	Condition Number
SA	1.4232	0.2974	0.7026	0.666215	2.71
Hf	1.2281	0.1857	0.8143	0.483897	3.74
χ	1.1691	0.1394	0.8606	1.042437	1.73
DMy	1.2669	0.2107	0.7893	1.807450	1.00

Since all VIF's are less than 10, multicollinearity is not a problem. All Condition Numbers less than 100. Multicollinearity is NOT a problem.

Table IX.  Significant molecular virtual fragments for the Set of 28 compounds. Molecules of analyzed database include 32 virtual fragments. The mass percents of 4 fragments are significant. THE MOST SIGNIFICANT VIRTUAL FRAGMENTS by square correlation of ‘the mass percent of fragment' and ‘Property values' are

Fragment atoms	Specimen (Com.no.)	Correlation sign	Square correlation
H2N	1	1	.3701
C2HN3S	2	− 1	.223
C6H4	4	1	.1751
HN	20	− 1	.1445

Correlation sign 1 means ‘large mass percent of this fragment increase the Property value’. Correlation sign − 1 means ‘large mass percent of this fragment decrease the Property value'.

Figure 1. Correlation of observed and calculated activity [log K_i (hCA XIV)] using PRECLAV descriptors (pca, ray, pon, and lhf).

Figure 2. Correlation of observed and calculated activity [log K_i (hCA XIV)] using Quantum chemical (HyperChem) descriptors (Hf, SA, X, Debys Y).