QligFEP: an automated workflow for small molecule free energy calculations in Q

Jespers, Willem; Esguerra, Mauricio; Åqvist, Johan; Gutiérrez-de-Terán, Hugo

doi:10.1186/s13321-019-0348-5

Journal of Cheminformatics

Table 2 Calculated and experimental relative binding free energies between pairs of the 16 CDK2 inhibitors, corresponding to the FEP pathways depicted in Fig. 2

From: QligFEP: an automated workflow for small molecule free energy calculations in Q

Ligand	Experiment^a	Calculated^b
		FEP+		QligFEP
		OPLS2005	OPLS3	OPLS2005	AMBER	CHARMM
1h1q	− 8.18	− 8.15 ± 0.00	− 7.56 ± 0.00	–	–	–
1h1r	− 7.67	− 8.52 ± 0.26	− 8.61 ± 0.17	− 8.04 ± 0.11	− 7.52 ± 0.31	− 9.75 ± 0.45
1h1 s	− 11.25	− 10.66 ± 0.40	− 10.14 ± 0.56	− 10.90 ± 0.28	− 11.07 ± 0.41	− 12.60 ± 0.72
1oi9	− 9.74	− 9.95 ± 0.32	− 9.66 ± 0.22	− 9.88 ± 0.16	− 10.40 ± 0.24	− 9.35 ± 0.49
1oiu	− 9.08	− 10.10 ± 0.24	− 9.50 ± 0.47	− 9.89 ± 0.26	− 10.81 ± 0.74	− 11.26 ± 0.63
1oiy	− 9.79	− 8.97 ± 0.29	− 8.94 ± 0.39	− 10.10 ± 0.23	− 10.82 ± 0.48	− 11.13 ± 0.52
17	− 7.04	− 8.56 ± 0.19	− 8.79 ± 0.13	− 7.99 ± 0.11	− 9.14 ± 0.51	− 10.63 ± 0.33
20	− 8.72	− 8.52 ± 0.33	− 7.96 ± 0.28	− 8.70 ± 0.18	− 8.60 ± 0.23	− 8.65 ± 0.37
21	− 7.83	− 8.50 ± 0.27	− 8.70 ± 0.15	− 7.54 ± 0.15	− 7.07 ± 0.35	− 11.11 ± 0.39
22	− 7.76	− 8.58 ± 0.23	− 9.00 ± 0.18	− 7.74 ± 0.15	− 6.68 ± 0.51	− 9.66 ± 0.47
26	− 8.43	− 9.44 ± 0.33	− 8.68 ± 0.39	− 9.57 ± 0.14	− 9.42 ± 0.44	− 10.31 ± 0.59
28	− 11.11	− 9.90 ± 0.49	− 10.31 ± 0.49	− 13.47 ± 1.10	− 5.45 ± 0.93	− 11.54 ± 0.89
29	− 9.88	− 9.53 ± 0.47	− 9.32 ± 0.61	− 13.59 ± 0.99	− 11.44 ± 1.18	− 11.55 ± 1.21
30	− 9.81	− 8.92 ± 0.38	− 9.13 ± 0.48	− 10.87 ± 0.60	− 11.48 ± 0.77	− 10.92 ± 0.50
31	− 9.54	− 8.19 ± 0.41	− 9.03 ± 0.46	− 8.75 ± 0.19	− 9.68 ± 0.48	− 10.83 ± 0.91
32	− 9.75	− 9.26 ± 0.47	− 10.27 ± 0.49	− 8.48 ± 0.84	− 9.77 ± 0.65	− 11.92 ± 0.93
R² [95% CI]		0.48 [0.09–0.78]	0.51 [0.11–0.79]	0.59 [0.20–0.84]	0.13 [0.01–0.52]	0.33 [0.01–0.69]
MAE		0.75 (0.69^c)	0.75 (0.79^c)	0.85	1.11	1.54
Slope		0.43	0.44	1.17	0.53	0.56
Intercept		− 5.22	− 5.06	1.08	− 4.39	− 5.47

^aExperimental ∆IC₅₀ values extracted from Ref. [71] and are transformed into ∆∆G_bind using the relation \(\Delta \Delta G_{bind,exp}^{o} = RTln\left( {\frac{{IC_{50} \left( B \right)}}{{IC_{50} \left( A \right)}}} \right)\)
^bAll energies are in kcal/mol, with standard error of the mean (SEM) estimated from replicate simulations for Q, and cycle closure errors for FEP+ [29]
^cMAE taken from Ref. [29], based on cycle closure correction

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