Table 2.

Free energy differences calculated for each stage of the alchemical thermodynamic cycle for compounds A1, A2, A3, A7.

Binding Free Energy (kcal/mol)		A1	A2 a	A3 a	A7 a
Free energy of decoupling and restraining the ligand in a complex	$-\Delta G_{elec+vdw+restr}^{prot}$	−49.5 ± 0.2	−35.2 ± 0.2 (14.3)	−32.9 ± 0.2 (16.6)	−39.4 ± 0.2 (10.1)
Coulomb term	$-\Delta G_{elec}^{prot}$	−30.2 ±0.1	−15.9 ± 0.1 (14.3)	−20.6 ± 0.1 (9.6)	−22.1 ± 0.1 (8.1)
van der Waals andrestraint term	$-\Delta G_{vdw+restr}^{prot}$	−19.3 ± 0.1	−19.3 ± 0.2 (0.0)	−12.3 ± 0.1 (7.0)	−17.3 ± 0.1 (2.0)
Free energy of decoupling the ligand in solution	$\Delta G_{elec+vdw}^{solv}$	31.4 ± 0.1	20.3 ± 0.1 (−11.1)	22.0 ± 0.1 (−9.4)	40.2 ± 0.1 (8.8)
Coulomb term	$\Delta G_{elec}^{solv}$	29.5 ± 0.1	18.1 ± 0.1 (−11.4)	21.5 ± 0.1 (−8.0)	37.1 ± 0.1 (7.6)
van der Waals term	$\Delta G_{vdw}^{solv}$	1.9 ± 0.1	2.2 ± 0.1 (0.3)	0.5 ± 0.1 (−1.4)	3.1 ± 0.1 (1.2)
Free energy for restraining the decoupled ligand in solution	$\Delta G_{restr}^{solv}$	7.3	6.7 (−0.6)	7.0 (−0.3)	6.8 (−0.5)
Total free energy of binding	$\Delta G_{bind}^0$	−10.8 ± 0.2	−8.2 ± 0.2 (2.6)	−4.0 ± 0.2 (6.8)	7.6 ± 0.2 (18.4)

Note:^a$\Delta G$ values relative to the compound A1 are listed in parentheses.