3D-QSAR CoMFA studies on sulfonamide inhibitors of the Rv3588c β-carbonic anhydrase from Mycobacterium tuberculosis and design of not yet synthesized new molecules

Figures & data

Figure 1. Structural details of benzene sulphonamide and diazenylbenzenesulfonamides as mtCA 2 inhibitor (index with asterisk * molecules of test set).

Table 1. Observed, estimated, residual, values of mtCA 2 inhibitory activity (A) for the molecules used in the calibration set for CoMFA (tripos standard region).

Compound no.	Obs.	Est.	Res.
1	2.011	1.985	0.026
2	2.068	2.043	0.0248
3	2.086	2.063	0.023
4	1.949	1.928	0.021
5	2.052	2.075	−0.023
6	2.075	2.096	−0.021
7	2.078	1.967	0.111
8	2.096	2.014	0.082
9	2.039	2.125	−0.086
10	2.028	2.009	0.019
11	2.068	2.040	0.028
12	2.027	2.164	−0.137
13	3.032	3.067	−0.0345
14	3.179	3.145	0.034
15	3.119	3.108	0.011
16	1.956	2.038	−0.082
17	2.00	1.95	0.05
18	1.946	1.972	−0.026
19	3.708	3.736	−0.028
20	3.559	3.612	−0.053
21	4	3.961	0.039
22	2.80	2.739	0.061
23	2.727	2.775	−0.048
24	3.242	3.181	0.061
25	3.211	3.205	0.006

Table 2. Observed log K_I, calculated log K_I and residual values of compound used in the test set for CoMFA (tripos region).

Compound no.	Obs.	Est.	Res.
2	2.068	2.021	0.047
4	1.949	1.924	0.025
6	2.075	2.253	−0.178
10	2.028	1.988	0.04
13	3.032	3.151	−0.119
22	2.80	3.009	−0.209
24	3.242	3.019	0.223

Figure 2. The chemical structure of prediction set molecules not yet synthesized having unknown observed values of activity (A).

Table 3. Estimated inhibitory activity (A) of mtCA 2 (Mycobacterium tuberculosis) inhibitors of not yet synthesized molecule.

Compound no.	Est.	Compound no.	Est.
1	3.954	6	4.072
2	4.002	7	4.083
3	3.136	8	3.907
4	3.804	9	3.779
5	3.217

Figure 3. Best fit conformation.

Figure 4. Alignment of molecule in database.

Figure 5. Observed versus estimated inhibitory activity (A) of calibration set.

Table 4. Summary of 3D-ASAR analysis on mtCA 2 inhibitors of CoMFA on tripos standard region.

PLS statistics	Calibration set (all compounds)	Training set
q^2 (leave-one-out cross-validated predicted power of model )	0.88	0.854
R^2(correlation coefficient squared of PLS analysis)	0.993	0.989
N (optimum number of components obtained from cross-validated PLS Analysis and the same used in final non cross-validated analysis)	3	2
SEE (SE of estimate)	0.058	0.079
F-test value (F-value)	239.097	723.316
Steric field contribution from CoMFA	0.58	0.59
Electrostatic field contribution from CoMFA	0.42	0.41
Predictive r^2 ()		0.934

Figure 6. Observed versus estimated inhibitory activity (A) of training set and test set.

Figure 7. The CoMFA the steric field, the green (stererically favorable) and yellow (sterically unfavorable) contours.

Figure 8. The CoMFA the electrostatic field, the red (negative charge favorable) and blue (positive charge favorable) contours.