A quantitative structure-activity relationship study for structurally diverse HIV-1 protease inhibitors: contribution of conformational flexibility to inhibitory activity

Figures & data

Table I.  HIV-1 protease inhibitors used in this study.

Compounds	PDB ID	Ki (nM)	Number of rotatable bonds	Reference
A76889	1HVL	0.112	19	[34]
A76928	1HVK	0.011	19	[34]
A77003	1HVI	0.012	19	[34]
A78791	1HVJ	0.004	19	[34]
AG1343	1OHR	2.0	9	[35]
AHA001	1AJX	12.2	10	[36]
AHA006	1AJV	19.1	10	[36]
GR126045	1HTF	4.5	12	[37]
GR137615	1HTG	0.11	16	[37]
KNI272	1HPX	0.0055	14	[38]
L735524	1HSG	0.38	11	[39]
L738317	2BPV	21.2	13	[40]
SB203238	1HBV	430	14	[41]
SB206343	1HPS	0.6	16	[42]
U89360E	1GNO	20	19	[43]
JE2147	1KZK	0.041	9	[44]

Figure 1 Chemical structures of HIV-1 protease inhibitors used a) as a training set, and b) as a test.

Table II.  Energy (kcal/mol) of the complexes with protonation at Asp25 or Asp25′^a.

Compounds	Asp25	Asp25′	Compounds	Asp25	Asp25′
A76889	2082.01	2078.12	GR137615	2078.36	2083.89
A76928	2068.05	2072.16	KNI272	2085.45	2089.39
A77003	2090.63	2095.08	L735524	2080.32	2085.50
A78791	2073.64	2078.00	L738317	2086.01	2092.35
AG1343	2035.91	2033.57	SB203238	2100.22	2100.10
AHA001	2090.32	2088.66	SB206343	2100.48	2101.71
AHA006	2124.63	2122.15	U89360E	2027.08	2027.36
GR126045	2075.22	2074.35	JE2147	2059.17	2053.11

^a States with figures in italics denote the Asp protonation state to be chosen for calculation.

Table III.  Calculated parameters for linear regression modeling.

Compounds	ΔEint (kcal/mol)	ΔSrot (kcal/mol)	ΔElig (kcal/mol)
A76889	− 60.91	5.915	5.982
A76928	− 65.47	5.915	7.223
A77003	− 65.42	5.915	5.417
A78791	− 61.70	5.915	4.441
AG1343	− 54.88	2.802	4.302
AHA001	− 49.75	3.113	1.766
AHA006	− 50.71	3.113	4.038
GR126045	− 46.21	3.736	2.297
GR137615	− 60.48	4.981	3.300
KNI272	− 54.25	4.358	4.026
L735524	− 60.90	3.424	5.157
L738317	− 54.62	4.047	7.321
SB203238	− 54.62	4.358	12.89
SB206343	− 56.19	4.981	3.490
U89360E	− 51.87	5.915	4.374
JE2147	− 59.45	2.802	5.226

Table IV.  Statistical results of linear regression models.

	ΔGexp	R^2	Q^2	SPRESS^a
Model-1	= 0.3139 × ΔEint +4.8756	0.580	0.500	1.594
Model-2	= 0.4407 × ΔEint + ΔSrot +7.4826	0.643	0.567	2.038
Model-3	= 0.3679 × ΔEint +0.4054 × ΔElig +5.8733	0.771	0.713	1.224

^a S_PRESS (kcal/mol) = the predictive residual error sum of squares.

Table V.  Experimental, calculated, and predicted free-energy differences.

Compounds	ΔGexp (kcal/mol)	ΔGcalc^a (kcal/mol)	Residual (kcal/mol)	ΔGcalc^b (kcal/mol)	Residual (kcal/mol)	ΔGcalc^c (kcal/mol)	Residual (kcal/mol)
A76889	− 14.16	− 14.25	− 0.086	− 13.45	0.712	− 14.11	0.048
A76928	− 15.59	− 15.68	− 0.082	− 15.46	0.137	− 15.29	0.308
A77003	− 15.54	− 15.66	− 0.120	− 15.43	0.106	− 16.00	− 0.459
A78791	− 16.22	− 14.49	1.726	− 13.79	2.424	− 15.03	1.192
AG1343	− 12.38	− 12.35	0.028	− 13.90	− 1.522	− 12.57	− 0.194
AHA001	− 11.26	− 10.74	0.519	− 11.33	− 0.069	− 11.71	− 0.453
AHA006	− 10.98	− 11.04	− 0.060	− 11.75	− 0.770	− 11.15	− 0.164
GR126045	− 9.82	− 9.63	0.189	− 9.15	0.672	− 10.20	− 0.377
GR137615	− 14.17	− 14.11	0.061	− 14.19	− 0.020	− 15.04	− 0.869
KNI272	− 16.02	− 12.15	3.870	− 12.07	3.957	− 12.45	3.570
L735524	− 13.21	− 14.24	− 1.030	− 15.93	− 2.721	− 14.44	− 1.231
L738317	− 10.53	− 12.27	− 1.741	− 12.54	− 2.013	− 11.25	− 0.725
SB203238	− 9.06	− 12.27	− 3.209	− 12.23	− 3.169	− 9.00	0.064
SB206343	− 13.12	− 12.76	0.359	− 12.30	0.821	− 13.39	− 0.263
U89360E	− 10.96	− 11.41	− 0.452	− 9.46	1.492	− 11.44	− 0.482
JE2147	− 14.78	− 13.79	0.996	− 15.91	− 1.134	− 13.88	0.902

^a Calculated using the Model-1 equation.

^b Calculated using the Model-2 equation.

^c Calculated using the Model-3 equation.

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