A common feature-based 3D-pharmacophore model generation and virtual screening: identification of potential PfDHFR inhibitors

Figures & data

Figure 1.  Chemical structures of pyrimethamine (1), cycloguanil (2), and WR99210 (3).

Figure 2.  Chemical structures of the training set compounds used for pharmacophore model generation.

Table 1.  Summary of the hypotheses generated by a Catalyst/HipHop run.

Hypothesis	Molecular features^a	Ranking score^b	Direct hit (DH)^c	Partial hit (PH)^d
1	ZHDD	255.74	011111111101111111110111	100000000010000000001000
2	ZHDD	253.50	011111111101111111110111	100000000010000000001000
3	ZHDD	252.88	011111111101111111110111	100000000010000000001000
4	ZHDD	252.48	011111111101111111110111	100000000010000000001000
5	RHDD	249.25	111111111111111111110110	000000000000000000001001
6	ZHDD	249.14	011111111101111111110111	100000000010000000001000
7	RHDD	246.00	111111111111111111110110	000000000000000000001001
8	RHDD	243.91	111111111111111111110110	000000000000000000001001
9	ZHDD	243.10	011111111101111111110111	100000000010000000001000
10	ZHDD	241.11	111111111111111111110110	000000000000000000001001

^aZ, hydrophobic aromatic; H, hydrophobic aliphatic; D, hydrogen bond donor; R, ring aromatic.

^bThe higher the ranking score, the less likely it is that the molecules in the set fit the hypothesis by a chance correlation. The best hypothesis shows the highest value.

^cDirect hit indicates whether (1) or not (0) a molecule in the training set mapped every feature in the hypothesis.

^dPartial hit indicates whether (1) or not (0) a particular molecule in the training set mapped all but one feature in the hypothesis. Numeration of molecules is from right to left in both DH and PH³⁴.

Table 2.  pIC₅₀, number of conformers, best-fit values, and ΔE values of the training set compounds.

Compound^a	pIC50^b	Conf.^c	Best-fit value^d				ΔE (kcal/mol) of conformation^e
			Hypo1	Hypo2	Hypo3	Hypo4	Hypo1	Hypo2	Hypo3	Hypo4
4	7.30	32	2.960	1.985	1.440	3.326	17.420	1.397	13.346	10.971
5	6.85	147	3.590	2.897	2.342	2.886	9.260	16.361	3.189	16.631
6	5.77	113	3.332	3.744	2.899	3.107	3.064	7.553	8.836	1.979
7	5.55	206	2.691	2.954	2.589	2.886	16.589	13.317	13.737	4.274
8	7.54	105	3.959	2.968	2.986	3.886	10.116	9.651	8.354	11.252
9	7.44	69	2.951	2.897	1.806	3.759	18.626	19.471	13.049	15.347
10	5.89	82	3.031	3.056	2.609	2.821	5.664	15.421	11.947	0.327
11	5.75	66	3.422	3.483	2.579	2.943	12.770	1.847	1.506	10.735
12	6.00	103	3.039	3.007	2.627	2.918	6.265	15.884	5.685	7.028
13	6.20	240	2.451	3.655	3.152	3.347	11.229	11.059	5.091	5.377
14	5.92	226	2.937	2.960	2.602	2.820	18.223	9.043	14.27	18.223
15	5.85	254	3.516	3.906	3.137	3.385	9.227	18.264	8.995	19.165
16	5.00	249	2.972	2.840	2.893	2.923	2.483	14.678	10.491	13.438
17	8.05	103	4.000	2.955	3.752	4.000	11.430	15.610	9.664	5.496
18	7.49	117	3.988	2.919	3.469	3.970	10.965	6.858	13.295	7.682
19	7.51	127	3.992	2.838	3.443	3.949	8.337	16.648	10.719	3.698
20	6.65	87	3.979	2.825	3.468	3.961	12.051	11.733	11.421	5.835
21	5.77	116	3.907	2.550	3.262	3.653	5.702	7.052	10.486	19.096
22	5.00	86	3.938	2.659	3.065	3.505	19.126	11.977	5.028	15.964
23	5.85	175	3.984	2.931	3.827	3.976	18.843	19.645	12.593	5.389
24	6.77	25	2.129	3.845	2.789	2.213	0.978	19.790	15.113	0.303
25	7.15	3	2.646	0.286	2.542	1.997	0.003	0.003	0.000	0.000
Pyrimethamine (1)	5.38	6	1.988	0.565	0.798	1.438	0.086	0.059	0.000	0.059
WR99210 (3)	8.57	158	3.868	3.494	3.899	3.898	9.027	6.845	4.231	9.449

^aIUPAC names of the compounds are given in ref. 27.

^bIC₅₀ (in nM ranges) values are given in ref. 27.

^cNumber of conformational models of training set compounds within the range of 20 kcal/mol from the global minimum.

^dBest-fit value of the conformer used for mapping.

^eEnergy difference between the conformer used for mapping and the global minimum calculated by Catalyst software³⁴.

Figure 3.  Mapping of 4 (a), 8 (b), 9 (c), 17 (d), 18 (e), 19 (f), and WR99210 (3) (g) onto hypo1. Pharmacophoric features are color-coded (violet, hydrogen bond donor; blue, hydrophobic aliphatic; light blue, aromatic hydrophobic).

Table 3.  Docking scores of hits identified from the virtual screening study.

S. no.	Hit	Glide	FlexX
		Gscore (Emodel)	FlexX score	G-score	PMF-score	D-score	ChemScore	C-score
1	NCI00043568	−11.34 (–64.5)^b	−24.78^a	−211.26	−73.26	−109.68	−40.28	4
2	NCI0029604	−10.21 (–54.6)^a	−23.82^a	−134.47	−72.56	−103.24	−26.30	5
3	GK03630	−10.05 (–65.3)^a	−19.43^a	−192.00	−55.54	−97.01	−26.11	5
4	GK03628	−9.96 (–59.4)^b	−17.14^a	−187.77	−15.10	−102.22	−24.27	3
5	NCI00129588	−9.92 (–63.7)^a	−19.96^a	−184.61	−68.31	−100.70	−24.03	5
6	CD00706	−9.53 (–62.5)^c	−24.64^a	−31.02	−11.97	−114.57	−33.07	4
7	NCI0027612	−9.26 (–50.2)^a	−23.11^a	−123.23	−72.94	−95.66	−24.72	5
8	NCI0037722	−8.69 (–61.6)^a	−23.35^a	−171.53	−47.26	−102.20	−29.30	5
9	NCI0014710	−6.33 (–51.6)^d	−22.40^d	−38.00	−64.64	−97.19	−26.18	2
	WR99210 (ref.)	−8.44 (–80.20)^a	−17.86^a	−209.23	−67.80	−134.79	−28.91	5

^aHydrogen bond interactions of hits with Ile14, Leu164, and Asp54.

^bHydrogen bond interactions of hits with Asp54, Asn108, and Ile14 or Leu164.

^cHydrogen bond interactions of hits with Asp54 and Ile14 or Leu164.

^dHydrogen bond interactions of hits with Asp54 and Asn108.

Figure 4.  Chemical structures of the identified hits.

Figure 5.  Mapping of NCI00043568 (a), GK-03628 (b), NCI0029588 (c), CD00706 (d), NCI0037722 (e), and NCI0014710 (f) onto hypo1. Pharmacophoric features are color-coded (violet, hydrogen bond donor; blue, hydrophobic aliphatic; light blue, aromatic hydrophobic).

Figure 6.  Stereoview of XPGlide predicted binding poses of (a) NCI004356, (b) GK03628, (c) NCI0029588, (d) CD00706, (e) NCI0037722, and (f) NCI0014710 in the active site of the quadruple-mutant PfDHFR enzyme. For the sake of clarity, only important amino acid residues are given.

Catalyst, Version 4.10. San Diego, CA: Accelrys Inc., 2005.

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