Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation

Figures & data

Table 1. Pharmacophores generated from the co-crystallized Hsp90 structure (2XJX and 4LWF).

Pharmacophore	Model	Number of features	Feature set*	Selectivity score
2XJX_2_01	Pharmacophore_01	5	DHHHP	9.7772
2XJX_2_02	Pharmacophore_02	5	AHHHP	8.8637
2XJX_2_03	Pharmacophore_03	4	DHHP	8.2624
2XJX_2_04	Pharmacophore_04	4	DHHP	8.2624
2XJX_2_05	Pharmacophore_05	4	DHHP	8.2624
2XJX_2_06	Pharmacophore_06	4	HHHP	7.3489
2XJX_2_07	Pharmacophore_07	4	AHHP	7.3489
2XJX_2_08	Pharmacophore_08	4	AHHP	7.3489
2XJX_2_09	Pharmacophore_09	4	AHHP	7.3489
2XJX_2_10	Pharmacophore_10	4	DHHH	6.8689
4LWF_2_01	Pharmacophore_01	5	ADDDH	10.622
4LWF_2_02	Pharmacophore_02	5	ADDDH	10.622
4LWF_2_03	Pharmacophore_03	5	AADDH	9.7088
4LWF_2_04	Pharmacophore_04	5	AADDH	9.7088
4LWF_2_05	Pharmacophore_05	5	AADDH	9.7088
4LWF_2_06	Pharmacophore_06	5	AADDH	9.7088
4LWF_2_07	Pharmacophore_07	4	ADDD	9.1076
4LWF_2_08	Pharmacophore_08	4	DDDH	9.1076
4LWF_2_09	Pharmacophore_09	4	ADDD	9.1076
4LWF_2_10	Pharmacophore_10	5	AAADH	8.7953

Bolded pharmacophores are the QSAR selected pharmacophores used as a searching queries.

*A: hydrogen bond acceptor; D: hydrogen bond donor; H: hydrophobe; P: positive ionizable; R: ring aromatic.

Table 2. Pharmacophoric features and corresponding weights, tolerances and 3D coordinates of generated pharmacophore from cocrystallized Hsp90 (2XJX_2_05).

		Chemical features
Model	Definition		Hbic1	Hbic2	HBD		PosIon
2XJX_2_05	Tolerances		1.60	1.60	1.60	2.20	1.60
	Coordinates	X	13.68	15.88	11.32	9.702	14.297
		Y	0.22	−5.6	−2.163	− 4.06	−4.266
		Z	9.48	3.86	11.12	12.786	0.628
Feature	X	Y	Z	Radius
ExcludedVolume_1.6	17.99	−9.955	1.538	1.27
ExcludedVolume_1.7	14.379	−9.186	6.516	1.368
ExcludedVolume_1.8	11.584	4.072	10.408	1.6
ExcludedVolume_1.9	11.629	−0.727	15.258	1.154
ExcludedVolume_1.10	17.657	1.522	4.208	1.27
ExcludedVolume_1.11	19.143	−9.665	7.247	1.454
ExcludedVolume_1.12	11.109	−7.504	3.428	1.53
ExcludedVolume_1.13	19.786	−6.747	9.056	1.27
ExcludedVolume_1.14	16.369	−5.262	13.14	1.368
ExcludedVolume_1.15	19.648	−2.737	9.129	1.454
ExcludedVolume_1.16	15.887	1.055	14.295	1.154
ExcludedVolume_1.17	16.132	3.478	9.757	1.154
ExcludedVolume_1.18	13.118	−8.426	12.278	1.27
ExcludedVolume_1.19	10.355	−3.364	7.132	1.53
ExcludedVolume_1.20	10.349	−7.583	9.559	1.454
ExcludedVolume_1.21	7.465	−2.365	11.724	1.454
ExcludedVolume_1.22	4.726	−8.104	−27.842	1.154
ExcludedVolume_1.23	−5.074	−14.009	−26.614	1.53
ExcludedVolume_1.24	−0.172	−11.579	−30.072	1.454

Table 3. Pharmacophoric features and corresponding weights, tolerances and 3D coordinates of generated pharmacophore from cocrystallized Hsp90 (4LWF_2_04).

		Chemical features
Model	Definition		HBD1		HBD2		Hbic
4LWF_2_04	Tolerances		1.60	2.20	1.60	2.20	1.60
	Coordinates	X	−4.016	−6.446	−0.634	− 0.653	1.76
		Y	−10.343	−11.582	−7.315	− 6.949	−12.38
		Z	−24.81	−23.561	−28.988	− 31.966	−23.5
			HBA1		HBA2
	Tolerances		1.60	2.20	1.60	2.20
	Coordinates	X	−1.273	0.808	−2.269	− 4.493
		Y	−12.44	−10.723	−9.029	− 10.62
		Z	−21.476	−20.164	−28.366	− 27.132
Feature	X	Y	Z	Radius
ExcludedVolume_1.6	17.99	−9.955	1.538	1.27
ExcludedVolume_1.7	14.379	−9.186	6.516	1.368
ExcludedVolume_1.8	11.584	4.072	10.408	1.6
ExcludedVolume_1.9	11.629	−0.727	15.258	1.154
ExcludedVolume_1.10	17.657	1.522	4.208	1.27
ExcludedVolume_1.11	19.143	−9.665	7.247	1.454
ExcludedVolume_1.12	11.109	−7.504	3.428	1.53
ExcludedVolume_1.13	19.786	−6.747	9.056	1.27
ExcludedVolume_1.14	16.369	−5.262	13.14	1.368
ExcludedVolume_1.15	19.648	−2.737	9.129	1.454
ExcludedVolume_1.16	15.887	1.055	14.295	1.154
ExcludedVolume_1.17	16.132	3.478	9.757	1.154
ExcludedVolume_1.18	13.118	−8.426	12.278	1.27
ExcludedVolume_1.19	10.355	−3.364	7.132	1.53
ExcludedVolume_1.20	10.349	−7.583	9.559	1.454
ExcludedVolume_1.21	7.465	−2.365	11.724	1.454
ExcludedVolume_1.10	0.475	−17.398	−25.583	1.154
ExcludedVolume_1.11	−1.187	−3.518	−27.257	1.154
ExcludedVolume_1.12	4.565	−12.764	−26.382	1.53

Table 4: NCI compounds with Hsp90 inhibitory values.

No	NCI*	2XJX_2_05†	4LWF_2_04‡	%Inhibition¶	IC50 μM	R^2
84	365351	2.772	2.551	94.7	5.0	0.997
85	687759	0.614	1.83	100	8.2	0.984
86	120626	3.241	1.441	100	9.0	0.957
87	180024	1.214	3.442	100	10.1	0.933
88	179203	2.723	2.016	100	11.3	0.994
89	123468	2.666	1.198	100	14.0	0.90
90	276751	1.847	1.668	79.0	15.8	0.991
91	736219	1.506	3.618	100	16.0	0.90
92	122060	2.559	1.936	100	18.9	0.981
93	111066	3.097	1.699	70.5	19.2	0.975
94	120924	1.072	1.346	87.5	22.0	0.999
95	112531	2.991	1.311	77.3	29.5	0.964
96	125844	2.868	1.682	73.8	40.2	0.90
97	736218	1.414	2.258	74.5	48.3	0.977
98	112534	3.187	1.181	53.4	77.1	0.993
99	134420	2.275	1.132	86.3	--	--
100	637992	2.921	1.193	57.9	--	--
101	268696	2.514	3.194	52.6	--	--
102	268708	0.634	2.657	51.3	--	--
103	124232	2.416	1.773	50	--	--
104	143491	3.546	2.862	48.7	--	--
105	112530	3.179	1.643	38.6	--	--
106	125845	1.292	1.599	21.3	--	--
107	652604	1.544	2.732	17.1	--	--
108	CCT018159^d	----	----	98.2	7.2	0.97

*NCI screened and bioassay hits.

† Hsp90 pharmacophoric model generated from cocrystallized structure.

‡ Percentage of inhibition at 100 μM concentration of inhibitor.

¶ Standard Hsp90 inhibitor with reported IC₅₀=5.7 μM42.

Figure 1. (A) 2XJX_2_05, the QSAR successful pharmacophore generated by DS studio 4.5, (B) cocrystallized XJX1232 in Hsp90 (2XJX, resolution 1.66 Å), (C) mapping of pharmacophore with cocrystallized Ligand XJX1232, (D) chemical structure of XJX1232.

Figure 2. (A) 4LWF_2_04, the QSAR successful pharmacophore generated by DS studio 4.5, (B) cocrystallized FJ3301 in Hsp90 (4LWF, resolution 1.75 Å), (C) mapping of pharmacophore with cocrystallized Ligand FJ3301, (D) chemical structure of FJ3301.

Figure 4. Two dimensional analysis of the cocrystallized ligand in the ATPase binding site of (A) Hsp90 (2XJX , resolution 1.66 Å) (B) Hsp90 (4LWF , resolution 1.75 Å), using DS 3.5 visualizer.

Figure 5. (A, D, G) Mapping compounds (84, 86, 88), respectively with 2XJX_2_05; cocrystallized pharmacophore generated by DS studio 4.5, (B, E, H) docked compounds (84, 86, 88), respectively in ATPase binding pocket of Hsp90 (2XJX, resolution 1.66 Å), (C, F, I) compounds (84, 86, 88) mapped and docked.

Figure 6. (A, D, G) Mapping compounds (84, 86, 88), respectively with 4LWF_2_04; cocrystallized pharmacophore generated by DS studio 4.5, (B, E, H) docked compounds (84, 86, 88), respectively in ATPase binding pocket of Hsp90 (4LWF, resolution 1.75 Å), (C, F, I) compounds (84, 86, 88) mapped and docked.

CCT018159, Tocris Bioscience, Bristol, BS11 9QD, UK; 2016. Available from: https://www.tocris.com/dispprod.php?ItemId=151522#.V6O01jsrLbI

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