A method to enhance the hit ratio by a combination of structure-based drug screening and ligand-based screening

Figures & data

Figure 1 Schematic representation of the screening methods in the current study. The same procedure was applied to models A and B. The protein set consists of the proteins listed in Appendixes A and B.

Table 1 q values and hit ratios for target protein models A and B

Proteina PDBb				q (%)
		RMSDc		Conventional		MTS&MASCd		DSMe		MSMf		ML-DSIg		Sumh		Consensusi
		A	B	A	B	A	B	A	B	A	B	A	B	A	B	A	B
HIVP	3hvp*	0.0	2.0	89.4	85.4	89.0	83.5	89.0	89.2	91.2	90.9	83.1	82.2	90.6	90.9	89.6	90.3
	1aid	1.4	1.8	85.3	87.6	86.9	87.5	88.8	89.6	91.7	91.7	80.0	83.4	92.4	91.5	90.5	90.2
	1hpx	2.3	2.6	95.4	80.2	94.7	81.5	94.3	89.7	92.2	92.0	84.4	80.6	91.8	91.4	90.7	91.6
	1htf1	2.4	2.3	88.9	87.7	82.0	83.2	92.5	90.6	91.0	90.5	83.3	85.9	90.9	90.4	92.8	91.5
	1htf2	2.4	2.0	83.2	87.2	71.9	80.0	93.0	90.7	92.2	92.7	77.4	75.6	91.9	91.5	91.8	91.3
	1ivp	2.2	2.5	82.7	64.4	74.8	49.5	90.9	49.5	91.0	91.4	80.4	77.6	91.0	91.2	91.0	90.0
	4phv	2.4	2.6	92.3	83.9	79.8	73.9	90.4	91.5	92.2	91.3	79.3	84.8	91.2	91.0	89.9	90.3
average				88.2	82.3	82.7	77.0	91.3	84.4	91.7	91.5	81.1	81.5	91.4	91.1	90.9	90.7
σq				4.4	7.7	7.5	11.9	1.9	14.3	0.5	0.7	2.3	3.5	0.6	0.4	1.0	0.6
COX2	5cox*	0.0	1.6	46.7	33.1	89.2	70.5	55.5	49.1	94.3	95.0	89.4	80.1	96.8	96.2	98.2	97.8
	1cx2	0.7	1.6	55.8	44.3	92.0	83.0	98.7	97.4	95.2	94.8	91.0	82.2	95.9	96.8	98.0	98.5
	1pxx	0.8	1.4	46.3	33.2	85.8	78.4	99.1	78.4	95.4	95.0	88.5	84.0	96.8	96.7	98.1	98.3
	4cox	0.6	1.3	45.0	16.4	82.2	52.9	95.6	31.7	97.4	95.7	99.5	89.0	96.5	97.2	98.5	98.6
	6cox	0.6	1.5	55.2	12.3	91.3	31.9	95.1	93.7	94.9	95.4	81.7	87.6	96.1	96.0	98.4	97.9
average				49.8	27.9	88.1	63.3	88.8	70.1	95.4	95.2	90.0	84.5	96.4	96.6	98.2	98.2
σq				4.7	11.8	3.7	18.8	16.7	25.6	1.0	0.3	5.7	3.3	0.3	0.4	0.2	0.5
THR	1l3f*	0.0	1.3	44.5	9.0	63.1	24.9	69.9	13.6	93.5	95.5	81.5	79.3	95.3	93.7	95.9	95.7
	1tlp	1.0	1.4	42.9	42.3	57.7	59.5	16.7	16.8	95.0	95.2	87.1	83.7	95.2	95.2	95.8	95.7
	1tmn	0.9	1.2	46.1	42.1	56.1	60.5	15.8	87.8	95.4	95.0	85.4	84.2	95.0	95.2	95.9	96.1
	2tmn	0.9	1.5	52.3	47.4	75.7	73.0	53.5	38.1	95.5	95.6	84.8	85.8	95.4	95.4	96.0	96.0
average				46.4	35.2	63.2	54.5	39.0	39.1	94.9	95.3	84.7	83.2	95.2	94.8	95.9	95.9
σq				3.6	15.3	7.7	17.9	23.5	29.7	0.8	0.2	2.0	2.4	0.1	0.7	0.1	0.2
GST	16gs*	0.0	2.6	69.3	72.7	50.8	60.9	28.0	24.2	86.3	85.8	82.3	82.4	91.6	92.8	92.7	94.3
	18gs	0.4	2.0	71.5	70.4	62.9	48.6	29.4	26.5	85.9	87.4	87.9	83.3	91.4	93.4	94.9	93.0
	2gss	0.3	1.3	67.4	70.4	54.3	59.7	26.5	28.8	87.8	86.1	86.0	85.9	92.4	93.7	93.3	95.5
	3pgt	0.5	1.7	68.2	63.8	46.4	34.7	25.0	23.3	87.5	88.1	82.5	77.7	92.1	92.3	94.7	94.9
average				69.1	69.3	53.6	51.0	27.2	25.7	86.8	86.9	84.6	82.3	91.9	93.1	93.9	94.4
σq				1.5	3.3	6.1	10.6	1.6	2.1	0.8	0.9	2.4	2.9	0.4	0.6	0.9	0.9
average	q value			66.4	56.7	74.3	63.9	67.4	60.0	91.7	91.4	81.4	83.7	92.9	92.5	93.6	93.4
hit ratio	at 1%			23.8	16.2	15.1	7.3	21.1	14.7	35.8	29.3	16.7	16.1	28.8	25.4	47.2	46.0

Notes: The q value is the area under the database enrichment curve. The q value is 50 for random screening and the maximum value is 100. The hit ratio is the hit ratio at the first 1% of the entries in the database. The σ_q value is the standard deviation of the q values. Model A includes the original crystal structures of the target proteins. Model B includes the model structures of the target proteins obtained by the MD simulations in explicit water.

a name of target protein.

b PDB code.

* represents apo structure.

c RMSD value from the apo structure of protein model A.

d combination of MTS and MASC methods (sum set) with original docking score.

e MTS method with the DSM method.

f MTS method with the MSM method (MSM-MTS method).

g ML-DSI method.

h sum set of predicted compounds by the MSM-MTS and the ML-DSI method.

i consensus set of predicted compounds by the MSM-MTS and the ML-DSI methods.

Figure 2 Database enrichment curves for models A and B. Filled circles, open circles, green squares, and red squares represent the results by the MSM-MTS method, the ML-DSI method, the sum sets of predicted compounds by the MSM-MTS and the ML-DSI methods, and the consensus sets of predicted compounds by the MSM-MTS and the ML-DSI methods, respectively. a: database enrichment curves for model A, in which the target protein structures are the original crystal structures. b: database enrichment curves for model B, in which the target protein structures are the model structures obtained by the MD simulations in explicit water.