Structure-activity relationships for a class of selective inhibitors of the major cysteine protease from Trypanosoma cruzi

Figures & data

Table I.  Chemical structures and corresponding pIC₅₀ values for a series of inhibitors of cruzain from Trypanosoma cruzi.

Training Set Inhibitors
Cpd	Structure	pIC50	Cpd	Structure	pIC50	Cpd	Structure	pIC50
1		6.55	10		7.30	19		6.70
2		5.15	11		7.70	20		7.22
3		6.85	12		5.00	21		6.34
4		6.55	13		5.41	22		7.30
5		5.55	14		6.25	23		5.72
6		5.00	15		5.00	24		6.70
7		5.00	16		5.89	25		7.10
8		5.55	17		6.49	26		6.57
9		6.66	18		6.32	27		6.64
28		7.22	34		5.00	40		5.00
29		7.15	35		5.00	41		5.00
30		7.10	36		5.80	42		5.00
31		5.00	37		6.00	43		5.00
32		5.00	38		5.85	44		5.00
33		5.00	39		5.00	45		5.00
Test Set Inhibitors
46		7.00	51		5.42
47		6.52	52		7.40
48		6.25	53		5.00
49		7.70	54		5.77
50		6.77	55		5.00

Figure 1.  General scaffold of thiosemicarbazone and semicarbazone derivatives.

Figure 2.  Distribution of pIC₅₀ values for the data set compounds.

Table II.  HQSAR analysis for various fragment distinctions on the key statistical parameters using fragment size default (4-7).

		Statistical Parameters
Model	Fragment Distinction	q^2	r^2	SEE	HL	PC
1	A/B	0.45	0.83	0.39	307	6
2	A/B/C	0.54	0.87	0.35	401	6
3	A/B/C/H	0.49	0.88	0.33	353	6
4	A/B/C/H/Ch	0.57	0.88	0.33	353	6
5	A/C	0.41	0.79	0.44	199	6
6	A/C/Ch	0.41	0.83	0.38	353	6
7	A/C/DA	0.24	0.49	0.65	97	3
8	A/C/H/Ch	0.38	0.73	0.49	151	4
9	A/C/Ch/DA	0.72	0.94	0.23	353	6
10	A/B/H	0.41	0.86	0.36	401	6
11	A/B/C/Ch	0.56	0.84	0.38	53	6
12	A/B/DA	0.27	0.52	0.64	83	4
13	A/B/C/DA	0.26	0.50	0.65	307	3
14	A/B/H/DA	0.52	0.80	0.42	353	5
15	A/B/C/H/DA	0.53	0.82	0.40	353	6
16	A/B/H/Ch/DA	0.67	0.92	0.27	151	6

q², cross-validated correlation coefficient; r², non-cross-validated correlation coefficient; SEE, non-cross-validated standard error; HL, hologram length; PC, optimal number of components. Fragment distinction: A, atoms; B, bonds; C, connections; H, hydrogen atoms; Ch, chirality; DA, donor and acceptor.

Table III.  HQSAR analysis for the influence of different fragment sizes on the statistical parameters.

			Statistical Parameters
Fragment Distinction	Model	Fragment Size	q^2	r^2	SEE	HL	PC
A/C/Ch/DA	17	2-5	0.67	0.86	0.36	59	6
	18	3-6	0.70	0.92	0.26	307	6
	19	4-7	0.71	0.94	0.23	353	6
	20	5-8	0.73	0.95	0.21	353	6
	21	6-9	0.75	0.96	0.20	401	6
	22	7-10	0.73	0.95	0.22	401	6

Table IV.  Experimental and predicted activities (pIC₅₀) with residual values for the test set inhibitors.

		HQSAR		Classical QSAR
Cpd	Experimental	Predicted	Residual^a	Predicted	Residual^a
46	7.00	6.75	0.25	6.59	0.41
47	6.52	6.51	0.01	6.60	− 0.08
48	6.25	5.81	0.44	6.52	− 0.27
49	7.70	7.97	− 0.27	7.53	0.17
50	6.77	6.91	− 0.14	6.75	0.02
51	5.42	5.62	− 0.20	5.62	− 0.20
52	7.40	7.25	0.15	6.98	0.42
53	5.00	4.85	0.15	4.93	0.07
54	5.77	5.78	− 0.01	6.35	− 0.58
55	5.00	5.15	− 0.15	4.97	0.03

^a The difference between experimental and predicted values.

Figure 3.  Plot of predicted values of pIC₅₀versus the corresponding experimental values for the training (open squares) and test (solid circles) set inhibitors for the final HQSAR model.

Figure 4.  HQSAR contribution map for the most potent cruzain inhibitor 11.

Figure 5.  Plot of predicted values of pIC₅₀versus the corresponding experimental values for the training (open squares) and test (solid circles) set inhibitors for the final classical QSAR model.

Figure 6.  Descriptors score to regression vector.