Table 1.

Structures, inhibition constants,⁷⁰ and the simulation results of the studied MMP-9 inhibitors.

No	X	R1	R2	log(1/Ki), Ki in M		−Δ<EvdW> a (kcal/mol)	−Δ<Eel> a (kcal/mol)	−Δ<EQM/MM> b (kcal/mol)		−Δ<SASA> (Å2)
				exp.	calc. d			Min	MD	Min c	MD a
1	X1	CH2CH3		8.297	8.035	111.93	189.63	1216.74	689.95	417.06	389.34
2 e	X1	CH2CH3		6.457	6.728	86.41	192.93	1177.15	489.14	324.51	311.53
3	X1	CH3		8.693	8.819	107.04	174.78	1130.66	860.87	350.53	411.94
4	X1			8.182	7.803	106.40	169.62	1105.70	721.32	425.77	343.59
5	X1			8.341	8.233	95.40	155.90	1140.95	520.52	437.80	496.27
6	X1			8.189	8.315	121.79	192.67	723.49	736.12	370.67	404.369
7	X1	(CH2)2N(CH2CH3)2		7.777	7.924	72.34	148.89	1107.33	646.02	455.69	395.52
8	X1			8.466	8.337	127.92	239.22	1090.74	533.07	460.21	504.04
9	X1	(CH2)2OCH2CH3		8.197	8.322	120.93	190.55	980.36	746.42	381.41	400.46
10	X1	CH2CH3		7.370	7.226	88.32	159.09	874.43	639.75	320.68	305.84
11	X1	CH2CH3		7.379	7.562	103.30	179.29	1016.72	696.22	353.45	323.61
12	X1	CH2CH3		7.285	7.253	88.67	192.33	879.98	614.65	303.00	321.47
13	X1	CH2CH3		7.096	7.017	90.80	182.57	868.42	589.55	316.57	302.09
14	X1	CH2CH3		7.493	7.122	98.18	176.21	879.45	595.82	322.45	312.99
15	X1	CH2CH3		6.556	7.218	87.85	156.83	887.22	608.37	348.26	319.82
16	X1	CH2CH3		7.020	7.635	95.44	183.74	982.55	696.22	334.14	333.28
17	X1	CH2CH3		7.228	7.224	94.51	159.36	949.87	595.82	319.49	326.53
18	X1	CH2CH3		7.848	8.158	123.38	183.20	1307.85	551.90	459.85	471.31
19	X1	CH2CH3		9.509	9.197	121.99	227.93	1127.44	940.95	429.04	423.94
20	X1	CH2CH3		10.10	10.18	123.45	206.88	1121.86	834.28	451.32	604.77
21	X1	CH2CH3		9.222	8.554	124.01	195.86	1058.55	740.15	456.49	434.23
22	X1	CH2CH3		10.00	9.977	137.04	224.55	1127.20	771.52	472.26	608.05
23	X1	CH2CH3		7.417	7.675	111.28	197.02	1037.06	771.52	389.28	302.73
24	X2	CH2CH3		7.959	8.114	0.74	0.82	1023.59	727.60	384.47	381.87
25	X3	CH2CH3		8.420	8.026	103.83	203.22	1013.16	683.67	361.72	391.05
26	X4	CH2CH3		8.947	9.193	110.63	189.12	1009.13	771.52	345.50	504.02
27	X5	CH2CH3		8.284	8.218	132.48	237.82	879.21	740.15	428.73	389.68
28	X6	CH2CH3		6.500	6.081	95.55	180.16	549.68	464.73	253.08	237.38

^aThe LR terms for van der Waals and electrostatic energies and for the SASA change were obtained using MD simulation with explicit solvent.

^bThe QM/MM energy terms calculated for optimized structures after QM/MM minimization and for time-averaged structures after MD simulation.

^cThe SASA change for optimized structures after QM/MM minimization.

^dCalculated from Eq. 3 with optimized values of adjustable parameters for Step 4 (Table 2, last row).

^eConfiguration of C-3 (marked with an asterisk) is S in 2 while in other compounds it is R.