Docking, CoMFA and CoMSIA studies of a series of sulfonamides derivatives as carbonic anhydrase I inhibitors

Figures & data

Table 1.  Structures and activities of aromatic sulfonamide derivatives.

Inhibitor	R	Ki(nM),hCA I
1	H	7.5
2	2-Me	107
3	3-Me	730
4	4-Me	104
5	2-F	621
6	3-F	116
7	4-F	108
8	2-Cl	640
9	3-Cl	311
10	4-Cl	112
11	2-Br	110
12*	3-Br	510
13*	4-Br	659
14*	3-OMe	342
15	F5	110
16	H	9
17	2-F	8.5
18	3-F	11.3
19	4-F	7.6
20	2-Cl	25.1
21	3-Cl	113
22	4-Cl	3.2
23	2-Br	43.4
24	3-Br	30.8
25	4-Br	12.3
26	2-Me	10.5
27*	3-Me	110
28*	4-Me	5.1
29	3-OMe	8.6
30	F5	9.7
31*		250
32		25

*Prediction set.

Figure 1.  Interaction among Zinc, protein residues and ligand.

Table 2.  The experimental K_i values, predicted K_i values (Pred.) and the residuals (Res.) of the training and test set compounds based on realignment method.

Compound no.	Experimental	CoMFA-RF		CoMSIA
		Pred.	Res.	Pred.	Res.
1	8.125	6.697	1.428	6.694	1.431
2	6.971	6.737	0.234	6.687	0.284
3	6.137	6.737	−0.600	6.702	−0.565
4	6.983	6.736	0.247	6.694	0.289
5	6.207	6.706	−0.499	6.673	−0.466
6	6.936	6.681	0.255	6.729	0.207
7	6.967	6.678	0.289	6.725	0.242
8	6.194	6.666	−0.472	6.719	−0.525
9	6.507	6.683	−0.176	6.726	−0.219
10	6.951	6.717	0.234	6.752	0.199
11	6.959	6.726	0.233	6.746	0.213
12*	6.292	6.734	−0.442	6.758	−0.466
13*	6.181	6.730	−0.549	6.755	−0.574
14*	6.466	6.753	−0.287	6.736	−0.270
15	6.959	6.74	0.219	6.731	0.228
16	8.046	7.901	0.145	7.903	0.143
17	8.071	7.911	0.160	7.937	0.134
18	7.947	7.909	0.038	7.909	0.038
19	8.119	7.906	0.213	7.912	0.207
20	7.600	7.665	−0.065	7.701	−0.101
21	6.947	7.667	−0.720	7.692	−0.745
22	8.495	7.685	0.810	7.695	0.800
23	7.363	7.936	−0.573	7.951	−0.588
24	7.511	7.925	−0.414	7.911	−0.400
25	7.910	7.934	−0.024	7.913	−0.003
26	7.979	7.928	0.051	7.943	0.036
27*	6.959	7.902	−0.943	7.876	−0.917
28*	8.292	7.916	0.376	7.901	0.391
29	8.066	7.751	0.315	7.586	0.480
30	8.013	7.914	0.099	7.904	0.109
31*	6.602	6.942	−0.340	6.947	−0.345
32	7.602	6.990	0.612	7.063	0.539

*Prediction set

Table 3.  Summary of the statistical results for the constructed models.^a

Statistical parameters	Rigid alignment		Realignment
	CoMFA-RF (cf = 3, vars = 1728)	CoMSIA (cf = 2.5, vars = 1728)	CoMFA-RF (cf = 3, vars = 1560)	CoMSIA (cf = 3, vars = 1560)
q^2	0.627	0.636	0.615	0.637
SEP	0.433	0.427	0.440	0.427
r^2ncv	0.706	0.713	0.701	0.713
SEE	0.384	0.380	0.387	0.379
Fratio	52.803	54.597	51.664	54.766
r^2pred	0.744	0.706	0.706	0.702
Component	1	1	1	1

^aThe q² values for all PC’s from 1 to 6 are the same and the PRESS value for the first PC’s is minimum.

Table 4.  Model progressive scrambling for CoMFA-RF and CoMSIA models based on realignment method.

Model	q^2	cSDEP	dq^2′/dr^2yy’
CoMFA-RF	0.475	0.478	0.900
CoMSIA	0.490	0.525	0.973

Figure 2.  CoMFA contour map displaying steric (a) and electrostatic (b) in combination with compound 27 and 22 respectively based on realignment method.

Figure 3.  CoMSIA contour map displaying steric (a), electrostatic (b), hydrophobic (c), hydrogen bond donor (d), hydrogen bond acceptor (f) in combination with 17, 17, 16, 16 and 23 respectively based on realignment method.