4D-QSAR Study of 17β-Hydroxysteroid Dehydrogenase Type 3 Inhibitors

Prostate cancer is one of the most common form of cancer among men, and its incidence has been increasing progressively. Since the prostate depends on androgenic hormones to regulate its growth and development, interference with androgenic biosynthesis are important to control the disease. Thus, in this work, a 4D-quantitative structure-activity relationship (QSAR) receptor independent study was carried out using the Laboratório de Quimiometria Teórica e Aplicada (LQTA)-QSAR approach and the new tool Web-4D-QSAR with a set of benzylidene oxazolidinedione and thiazolidinedione inhibitor of the 17β-hydroxysteroid dehydrogenase type 3. The obtained model is robust, free from chance correlation, and with good predictability in all tests performed. In addition to this result, a good mecanistic interpretation related to the binding with the biological target could be traced, which strengthens its potential application in virtual screening and design of new inhibitors of the studied enzyme with the possibility of use in the pharmacological treatment of prostate cancer.

Keywords:
prostate cancer; 17β-HSD3; computer-aided drug design; Web-4D-QSAR

Authorship

João Paulo A. Martins ^** e-mail: joaopauloam@ufmg.br

Departamento de Química, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte-MG, BrazilUniversidade Federal de Minas GeraisBrazilBelo Horizonte, MG, BrazilDepartamento de Química, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte-MG, Brazil

https://orcid.org/0000-0002-1036-5965

Eduardo B. de Melo

Laboratório de Química Medicinal e Ambiental Teórica, Universidade Estadual do Oeste do Paraná, 85819-110 Cascavel-PR, BrazilUniversidade Estadual do Oeste do ParanáBrazilCascavel, PR, BrazilLaboratório de Química Medicinal e Ambiental Teórica, Universidade Estadual do Oeste do Paraná, 85819-110 Cascavel-PR, Brazil

* e-mail: joaopauloam@ufmg.br

SCIMAGO INSTITUTIONS RANKINGS

Figures | Tables | Formulas

Figures (8)
Tables (3)
Formulas (5)

Compound	R₁	R₂	R₃	X₁	X₂	pIC₅₀
1	4-OCH₃–Ph–	3-Br–4-OH–Ph–	H	S	S	7.85
2	CH₃	3-Br–4-OH–Ph–	H	S	S	6.05
3	allyl	3-Br–4-OH–Ph–	H	S	S	6.92
4	propargyl	3-Br–4-OH–Ph–	H	S	S	6.52
5	CH₃OCH₂CH₂	3-Br–4-OH–Ph–	H	S	S	6.72
6	C₆H₁₁	3-Br–4-OH–Ph–	H	S	S	8.52
7	tetrahydropyran-4-yl	3-Br–4-OH–Ph–	H	S	S	7.12
8	4-OCH₃–Ph–	3-Br–4-OH–Ph–	H	S	S	7.05
9	4-OCH₃–Ph–	3-Br–4-OH–Ph–	H	S	O	7.89
10	Ph–	3-Br–4-OH–Ph–	H	S	O	8.22
11	3-OCH₃–Ph–	3-Br–4-OH–Ph–	H	S	O	8.15
12	2-OCH₃–Ph–	3-Br–4-OH–Ph–	H	S	O	7.22
13	3,4-OCH₂O–Ph–	3-Br–4-OH–Ph–	H	S	O	8.10
14	4-F–Ph–	3-Br–4-OH–Ph–	H	S	O	8.70
15	4-Cl–Ph–	3-Br–4-OH–Ph–	H	S	O	8.22
16	4-CH₃–Ph–	3-Br–4-OH–Ph–	H	S	O	8.70
17	4-CF₃–Ph–	3-Br–4-OH–Ph–	H	S	O	8.52
18	4-CN–Ph–	3-Br–4-OH–Ph–	H	S	O	7.72
19	4-OCH₃–Ph–	3-Br–4-OH–Ph–	H	O	O	7.64
20	4-COOCH₃–Ph–	3-Br–4-OH–Ph–	H	O	O	7.62
21	4-C(O)NHCH₃–Ph–	3-Br–4-OH–Ph–	H	O	O	7.25
22	4-C(O)N(CH₃)₂–Ph–	3-Br–4-OH–Ph–	H	O	O	7.60
23	4-C(O)–piperizine–Ph–	3-Br–4-OH–Ph–	H	O	O	7.38
24	4-C(O)–morphorine–Ph–	3-Br–4-OH–Ph–	H	O	O	6.52
25	4-N(CH₃)₂–Ph–	3-Br–4-OH–Ph–	H	O	O	7.60
26	4-NHAc–Ph–	3-Br–4-OH–Ph–	H	O	O	7.24
27	4-NHCO–(c-hex)	3-Br–4-OH–Ph–	H	O	O	7.68
28	4-SCH₃–Ph–	3-Br–4-OH–Ph–	H	O	O	7.05
29	4-SO₂CH₃–Ph–	3-Br–4-OH–Ph–	H	O	O	6.05
30	pyridin-2-yl	3-Br–4-OH–Ph–	H	O	O	7.13
31	pyridin-3-yl	3-Br–4-OH–Ph–	H	O	O	7.67
32	4-OCH₃–pyridin-3-yl	3-Br–4-OH–Ph–	H	O	O	8.40
33	4-CH₃–pyridin-3-yl	3-Br–4-OH–Ph–	H	O	O	7.17
34	4-F–pyridin-3-yl	3-Br–4-OH–Ph–	H	O	O	7.68
35	4-Cl–pyridin-3-yl	3-Br–4-OH–Ph–	H	O	O	7.70
36	4-N(CH₃)₂–pyridin-3-yl	3-Br–4-OH–Ph–	H	O	O	8.40
37	4-OCH₃–Ph–	4-OH–Ph–	H	S	S	6.91
38	4-OCH₃–Ph–	3-CH₃–4-OH–Ph–	H	S	S	7.70
39	4-OCH₃–Ph–	3-OCH₃–4-OH–Ph–	H	S	S	6.60
40	4-OCH₃–Ph–	3-F–4-OH–Ph–	H	S	S	8.70
41	4-OCH₃–Ph–	3-Cl–4-OH–Ph–	H	S	S	8.40
42	4-OCH₃–Ph–	2-Cl–4-OH–Ph–	H	S	S	8.30
43	4-OCH₃–Ph–	3,5-Cl–4-OH–Ph–	H	S	S	7.92
44	4-OCH₃–Ph–	3,5-F–4-OH–Ph–	H	S	S	8.30
45	4-OCH₃–Ph–	3-Cl–4-OH–5-F–Ph–	H	S	S	9.00
46	4-OCH₃–Ph–	4-OH–pyridin-2-yl	H	S	S	7.05
47	4-OCH₃–Ph–	4-OH–3-Br–pyridin-2-yl	H	S	S	7.40
48	4-OCH₃–Ph–	3-Br–4-OH–Ph–	CH₃	S	S	7.05
49	4-OCH₃–Ph–	3-Br–4-OH–Ph–	H	S	S	7.05

Parameter	Value
N	39
R²	0.77
RMSEC	0.35
F (cF)	60.98
Q²_LOO	0.61
RMSECV	0.44
Average r_m²(LOO)-scaled	0.50
∆r_m²(LOO)-scaled	0.14
R²-Q²_LOO	0.16
R²_pred	0.74
RMSEP	0.35
Average r_m²(pred)-scaled	0.61
∆r_m²(pred)-scaled	0.20
k	1.00
k’	0.10
\|R²₀ – R’²₀\|	0.13

Compound	Molecular descriptor								Pred. pIC₅₀	Prediction quality
Compound	20_17_17_LJ	11_10_12_C	18_24_22_LJ	17_15_15_LJ	19_10_19_LJ	10_18_23_C	20_17_16_LJ	12_21_17_C	Pred. pIC₅₀	Prediction quality
50	142.87	0.66	–0.15	141.03	27.92	–4.24	144.57	–71.64	5.86	moderate
51	135.55	–5.27	–0.09	184.04	–1.02	0.32	127.22	–9.59	8.31	moderate
52	132.28	0.49	–0.84	155.76	32.42	–5.65	136.92	–46.99	6.87	moderate
53	151.23	8.40	–1.10	157.02	–0.57	–26.02	149.28	–18.65	6.13	moderate
54	147.13	10.64	–0.61	166.03	133.41	–2.93	147.17	–15.18	6.97	moderate
55	152.72	–1.86	–0.16	173.34	135.89	–2.16	155.34	–7.86	7.69	moderate
56	132.55	–2.84	–0.14	173.34	131.15	–14.66	135.05	–79.27	6.46	moderate
57	18.06	–0.73	3.95	156.91	42.30	0.44	133.42	–35.47	7.87	moderate