Kinetic, thermodynamic and statistical studies on the inhibition of adenosine deaminase by aspirin and diclofenac

Figures & data

Figure 1 Double reciprocal Lineweaver–Burk plots for kinetics of 0.94 nM ADA at pH = 7.5 in the presence of 0.0 (▪), 7.5? (▪), 15.0 (▴), 22.5 (▵) and 30.0 μM (() of (a) aspirin at 27°C and (b) diclofenac at 37°C. Inset of each figure (secondary plots): apparent Michaelis constant, K'_m (K_m,app) versus concentration of inhibitor, [I].

Figure 2 ΔH^o versus K_I for first 10 injections, according to Equation (2) for (a) aspirin (b) diclofenac. The coordinates of intersection point of curves give true values for ΔH^o and K_I.

Scheme 1 Molecular structure of a) nucleoside and b) non-nucleoside inhibitors.

Table I.  List of descriptors used in this work.

Descriptor	Definition	Correlation coefficient with logKI
UI	Unsaturation index	− 0.775
HY	Hydrophilic factor	− 0.089
ARR	Aromatic ratio	− 0.401
MR	Ghose-Crippen molar refractivity	− 0.907
PSA	Fragment-based polar surface area	− 0.726
MLOGP	Moriguchi octanol-water partition coeff. (logP)	− 0.608
HOMA	Harmonic Oscillator Model of Aromaticity index	− 0.119
RCI	Jug RC index	− 0.537
AROM	Aromaticity (trial)	− 0.25
HOMT	HOMA total (trial)	− 0.879
L/BW	Length-to-breadth ratio by WHIM	0.239
RGYR	Radius of gyration (mass weighted)	0.429
SPH	Spherosity	− 0.04
ASP	Asphericity	− 0.452
FDI	Folding degree index	− 0.101
MUX	Dipole moment in X direction	0.332
MUY	Dipole moment in Y direction	0.519
MUZ	Dipole moment in Z direction	− 0.838
MUTOT	Total dipole moment	− 0.728
SA	Surface area	− 0.854
VOL	Molecular volume	− 0.874
HE	Hydration energy	0.036
POL	Polarizability	− 0.89
MW	Molecular weight	− 0.896

Table II.  Values of descriptors was calculated by Hyperchem-7.0 and Dragon-3.0.

NO	LogKI (Exp)	LogKI (Pred1)	LogKI (Pred2)	LogKI (Pred3)	UI	HY	ARR	MR	PSA	MLOGP	HOMA	RCI	AROM	HOMT
1	0.50	0.54	0.38	0.34	4.64	0.88	0.56	117.8	113.39	1.20	0.89	1.42	0.95	19.5
2	1.11	1.36	1.31	1.43	4.17	1.81	0.53	88.51	87.09	− 0.43	0.85	1.43	0.93	13.62
3	− 0.10	0.12	0.14	0.07	4.70	0.23	0.52	127.0	139.69	1.64	0.89	1.43	0.95	19.48
4	1.56	1.50	1.29	1.43	4.17	1.81	0.53	88.51	87.09	− 0.43	0.85	1.43	0.93	13.59
5	2.00	1.67	1.65	1.67	3.70	1.17	0.37	77.49	113.39	− 1.21	0.77	1.42	0.89	7.66
6	2.15	2.07	1.91	2.15	3.59	2.06	0.42	68.34	87.09	− 1.75	0.75	1.43	0.88	7.49
7	1.89	2.00	2.22	2.08	3.46	0.42	0.44	70.42	47.90	0.22	0.65	1.42	0.87	6.54
8	1.96	1.93	2.18	1.99	3.46	0.39	0.42	75.02	47.90	0.48	0.65	1.42	0.87	6.54
9	1.84	1.76	2.07	1.78	3.46	0.33	0.39	84.23	47.90	0.97	0.65	1.42	0.88	6.50
10	1.72	1.59	2.01	1.66	3.46	0.30	0.37	88.83	47.90	1.21	0.66	1.42	0.89	6.64
11	2.16	2.20	2.36	2.19	2.32	1.36	0.10	54.48	43.07	− 2.15	0.83	1.40	0.9	1.66
12	2.49	2.42	2.44	2.44	2.32	0.03	0.14	42.59	41.79	− 0.86	0.95	1.40	0.95	1.90
13	2.45	2.30	2.39	2.49	2.32	1.51	0.18	49.54	30.71	− 1.17	0.89	1.40	0.91	2.66
14	2.30	2.65	2.49	2.43	2.32	0.03	0.14	42.59	56.41	− 0.86	0.95	1.40	0.95	1.90
15	2.53	2.43	2.42	2.33	2.32	− 0.56	0.13	47.49	45.03	− 0.52	0.95	1.40	0.95	1.90
16	2.58	2.55	2.37	2.72	3.46	− 0.04	0.59	58.18	60.79	− 0.08	0.70	1.42	0.89	7.02
17	2.86	3.06	2.45	2.75	3.46	1.45	0.59	56.07	60.79	− 1.14	0.70	1.42	0.89	7.02
18	2.10	2.04	2.11	1.98	3.00	− 0.11	0.55	40.83	17.07	1.06	0.98	1.40	1.00	5.85
19	1.62	1.44	1.77	1.69	3.17	− 0.67	0.46	43.95	43.37	1.7	0.98	1.4	1	5.89
20	1.75	1.77	1.50	1.83	3.81	− 0.24	0.60	76.95	17.07	3.99	0.98	1.41	1	11.72

Table II. continued. 

L/BW	RGYR	SPH	ASP	FDI	MUX	MUY	MUZ	MUTOT	SA	VOL	HE	POL	MW
0.91	0.25	0.93	0.81	1.60	0.571	− 0.081	8.853	8.872	715	1245	− 14.93	49.04	475
0.86	0.56	0.93	0.78	6.30	− 1.222	0.243	5.854	5.985	572	972	− 17.53	37.46	371
0.80	0.31	0.91	0.82	2.60	− 2.868	− 3.85	7.334	8.766	730	1315	− 14.19	52.79	517
0.83	0.50	0.94	0.68	5.10	− 0.837	− 1.213	5.284	5.486	579	985	− 17.00	37.00	371
0.76	0.39	0.95	0.89	3.70	− 2.752	− 0.305	5.486	6.145	556	934	− 12.57	33.00	351
0.80	0.38	0.96	0.85	3.40	− 0.588	− 1.277	4.790	4.990	495	822	− 15.16	29.60	309
0.73	0.47	0.95	0.83	6.20	0.253	− 0.121	3.154	3.167	489	808	− 9.50	30.04	274
0.74	0.49	0.94	0.91	6.60	0.12	0.310	3.171	3.188	508	851	− 9.01	31.88	288
0.75	0.54	0.94	0.91	7.70	− 0.014	0.637	3.106	3.171	550	928	− 8.36	35.55	316
0.76	0.58	0.94	0.86	9.10	− 0.035	0.613	3.101	3.161	569	969	− 8.14	37.38	330
5.30	5.08	0.67	0.43	0.97	− 3.17	6.744	− 1.275	7.563	431	694	− 18.24	23.81	268
1.70	3.24	0.94	0.30	1.00	4.194	1.194	− 0.328	4.373	340	522	− 41.60	17.04	180
4.30	5.03	0.80	0.46	0.99	− 4.146	3.706	− 1.330	5.675	431	658	− 17.41	20.99	225
1.40	3.17	0.94	0.26	1.00	3.371	0.810	− 0.110	3.469	339	522	− 4.88	17.04	180
1.50	3.56	0.94	0.27	1.00	3.864	0.566	− 0.068	3.906	364	573	− 1.36	18.87	194
0.74	0.46	0.98	0.82	5.20	− 0.16	2.328	0.472	2.381	449	705	− 7.05	24.83	241
0.76	0.46	0.95	0.62	4.90	0.835	0.675	− 0.059	1.076	443	696	− 12.01	24.25	222
6.10	3.38	0.88	0.59	0.96	3.093	− 1.622	0.315	3.506	327	492	− 11.20	16.18	151
1.4	3.3	0.73	0.15	0.95	3.05	− 3.041	− 1.261	4.74	348	535	− 8.95	17.38	180
2.2	5.12	0.78	0.25	0.95	− 2.568	0.804	− 0.658	2.771	461	767	− 8.18	29.69	296

Figure 3 The linear correlation between the experimental values of logK_I and the related values of the prediction set by MLR analysis on descriptors.

Table III.  Rotated component matrix for studied descriptors.

	Components
Descriptor	Size	Shape	Electronic
MW	0.965
MR	0.944
HOMT	0.942
VOL	0.941
POL	0.938
SA	0.934
MUZ	0.889
UI	0.888
PSA	0.831
MUTOT	0.679	− 0.525
RCI	0.606
HOMA		− 0.914
FDI		0.89
AROM		− 0.826
RGYR	− 0.547	− 0.731
ASP	0.525	0.721
SPH		0.659
LB/W		− 0.597
MLOGP			0.802
HY			− 0.73
MUX			0.653
ARR			0.569
MUY			− 0.54
HE

Table IV.  Specification of the multiple linear regression model for factors.

	Total		Non-nucleosides		Nucleosides
	Coefficient (error)	Mean effect	Coefficient (error)	Mean effect	Coefficient (error)	Mean effect
Constant	1.874 ( ± 0.057)		2.298 ( ± 0.058)		1.526 ( ± 0.066)
Size factor (F1)	− 0.641 ( ± 0.059)	− 0.904	0.0852 ( ± 0.022)	0.211	− 0.704 ( ± 0.069)	− 0.964
Shape factor (F2)	0.151 ( ± 0.047)	0.213	0.303 ( ± 0.062)	0.750	− 0.0598 ( ± 0.044)	− 0.082
Electronic factor (F3)	− 0.118 ( ± 0.023)	− 0.166	− 0.213 ( ± 0.016)	− 0.526	− 0.04 ( ± 0.01)	− 0.055
	R = 0.94, F = 43, S.E = 0.25		R = 0.94, F = 12.7, S.E = 0.17		R = 0.969, F = 35, S.E = 0.21

Figure 4 Correlation coefficients logK_I and descriptors for nucleoside (black) and non-nucleoside (white) bar line.