Journal of Chemical Information and Modeling
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2025
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IF 5.3
Sijie Liu,Jie Wu,Ya Chen,Clemens Alexander Wolf,Matthias Bureik,Johannes Kirchmair,Mario Andrea Marchisio,Gerhard Wolber
The human cytochrome P450 19A1 (CYP19A1, aromatase) is a heme-containing protein catalyzing the final steps of the biosynthesis of the steroid hormone 17β-estradiol. It is a key target for the treatment of sex-hormone-related disorders due to its role in mediating the conversion of androgens to estrogens. Here, we report the development of a virtual screening workflow incorporating machine learning and structure-based modeling that has led to the discovery of new CYP19A1 inhibitors. The machine learning models were built on comprehensive CYP19A1 data sets extracted from the ChEMBL and PubChem Bioassay databases and subjected to thorough validation routines. Ten promising hits that resulted from the virtual screening campaign were selected for experimental testing in an enzymatic assay based on heterologous expression of human CYP19A1 in yeast. Among the seven structurally diverse compounds identified as new CYP19A1 inhibitors, compound 9, a novel, noncovalent inhibitor based on coumarin and imidazole substructures, stood out by its high potency, with an IC50 value of 271 ± 51 nM.
研究领域:
药物化学
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计算生物学
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内分泌学
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Tiantian Fu,Bingyi Yao,Yuanqing Guo,Yujia Yang,Junze Huang,Chenmeizi Liang,Yuanjin Zhang,Xin Wang
Patients with eclampsia are treated with antihypertensive drugs such as nifedipine and sedatives like chlorpromazine. The placenta, a unique organ connecting mother and baby, can regulate the intake and export of substances and mediate their metabolism. This report examined the metabolism of nifedipine in human placenta microsomes, with K m and V max values of 12.90 ± 1.01 μM and 39.33 ± 0.88 pmol/mg protein/min, respectively. Further research demonstrated that cytochrome P450 19A1 (CYP19A1) was the primary enzyme responsible for metabolizing nifedipine in the placenta, confirmed through selective inhibition, Jarrett (JAR) cell verification, recombinant enzyme identification, and metabolism correlation analysis using the CYP19A1-specific substrate androstenedione. Additionally, this study investigated the effect of chlorpromazine on nifedipine metabolism in the placenta. The results indicated that chlorpromazine competitively inhibited CYP19A1 activity in human placenta microsomes and CYP19A1 supersomes, thus decreasing nifedipine metabolism mediated by this enzyme. In brief, this study confirms that nifedipine is metabolized in the human placenta and can interact with chlorpromazine via CYP19A1-mediated pathways in in vitro conditions.
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高影响因子
Veterinary Sciences
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2025
·Vol. 12
·期 5
·428
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IF 2.3
Yanbing Lou,Tingting Yang,Chenglong Xia,Shijun Yang,Huidan Deng,Yanqiu Zhu,Jing Fang,Zhicai Zuo,Hongrui Guo
Simple SummaryYak, as a unique species of plateau cattle, is highly susceptible to Cu deficiency, which is further exacerbated by poor soil conditions and low nutrient content in yak feed, which is associated with the decline of yak performance. Hormones synthesized by granulosa cells of yak follicles play an indispensable role in reproductive function. In this study, we investigated the effects of different concentrations of copper on the hormone secretion of cultured granulosa cells of yak follicles and the related molecular mechanisms. The above results showed that copper could positively promote the hormone secretion of female yaks, which provided a strategy direction with potential value for improving the fertility of yaks under the condition of copper deficiency.Yak (Bos grunniens) is the main economic animal growing in the Qinghai–Tibet Plateau. Because of its poor growing environment, copper deficiency is common. Studies have shown that appropriate copper supplementation can improve the reproductive performance of heifers. In this study, the primary granulosa cells of yak were isolated, and different copper levels were established by adding copper chelator and copper sulfate. Biochemical, Western blot and transcriptome methods were used to reveal the mechanism of copper on the hormone secretion function of granulosa cells. The results showed that copper promoted hormone secretion by regulating the expression of steroid synthase such as StAR, CYP19A1 and CYP11A1. Transcriptome analysis showed that copper ion levels significantly affected the function of cells, and changes in copper ion level affected genes related to protein phosphorylation, lipid metabolism, lipid biosynthesis, steroid hormone synthesis and the MAPK pathway. In conclusion, copper can promote steroid hormone synthesis in the granulosa cells of yak follicles, and the MAPK signaling pathway may be involved.
研究领域:
动物科学
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生殖生物学
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分子生物学
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营养学
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Chaochao Gong,Zhuoqi Chen,Yunbing Tang,Han Lu,Sailing Chen,Yang Zhu,Ren-shan Ge,Junzhao Zhao
Aromatase (CYP19A1), a pivotal enzyme in the biosynthesis of estradiol from testosterone, is predominantly expressed in reproductive tissues including placentas. This study investigated the effects of paraben acid and nine parabens on the activity of human and rat CYP19A1 using microsomes derived from human and rat placentas and on estradiol secretion in human choriocarcinoma BeWo cells. The results showed that propyl, butyl, hexyl, heptyl, and nonyl parabens significantly inhibited human CYP19A1 activity, with IC 50 values of 66.37, 61.08, 55.65, 48.26, and 27.24 μM, respectively. In BeWo cells, these parabens notably diminished estradiol secretion at concentrations of 100 μM. Similarly, rat CYP19A1 was inhibited by these parabens, with IC 50 values of 98.07, 70.10, 41.30, 27.93, and 6.33 μM for propyl, butyl, hexyl, heptyl, and nonyl parabens, respectively. Kinetic analysis identified these compounds as mixed inhibitors. Bivariate correlation analysis revealed a negative correlation between the partition coefficient value, molecular weight, the number of carbon atoms in the alcohol moiety, as well as heavy atom number and IC 50 values. Three-dimensional quantitative structure-activity relationship analysis highlighted the critical role of hydrophobic regions in determining inhibitory potency. Docking studies suggested that parabens interact with the heme-iron binding site of both human and rat CYP19A1. This study elucidates the inhibitory effects of various parabens on CYP19A1 and their binding mechanisms, thereby providing a deeper understanding of their potential impact on estrogen biosynthesis.
研究领域:
药理学
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毒理学
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生殖生物学
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分子生物学
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计算化学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2022
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IF 5.195
Ying-Li Cai,Feng Zhang,Xiu-Xiu Dou,Hua-Wu Zeng,Gao-Song Wu,Yan-Lin Liang,Xi-Ke Xu,Jing Zhao,Ji Ye,Wei-Dong Zhang
Ethnopharmacological relevance Dingkun Pill (DKP), a traditional Chinese medicine prescription, was modified from Bujing decoction and Xusijiangsheng pill by the imperial physician in the Qing dynasty (1700′ s). It was believed to treat various gynecological diseases by nourishing qi and blood. Accumulating evidence indicates that it is effective in treating polycystic ovary syndrome (PCOS). However, the therapeutic efficacy and mechanism of action DKP against PCOS need to be further elucidated. Aim of the study To investigate the therapeutic effect and action mechanism of DKP against PCOS using an integrated approach of metabolomics and network pharmacology . Materials and methods The rat model of PCOS was established by dehydroepiandrosterone . An integrated metabolomics and network pharmacology strategy was applied to systemically clarify the mechanism of DKP against PCOS. Theca cells were prepared to evaluate the effect of DKP and its ingredients on testosterone synthesis in vitro. Results The pharmacological experiments demonstrated that DKP could effectively convert the disordered estrous cyclicity, decrease the level of testosterone and the luteinizing hormone/follicle stimulating hormone ratio, and inhibit abnormal follicle formation in PCOS rats. By metabolomics analysis, 164 serum endogenous differential metabolites and 172 urine endogenous differential metabolites were tentatively identified. Steroid hormone biosynthesis and ovarian steroidogenesis were the most significantly impacted pathways. Based on network pharmacology and metabolomics studies, the ingredient-target-pathway network of DKP in the treatment of PCOS was constructed. Among the 10 key targets, CYP17A1 , CYP19A1 , STS, AR, ESR1, and MYC were closely involved in ovarian androgen synthesis. In theca cell-based assay of testosterone synthesis, DKP and its two active compounds (ligustilide and picrocrocin) showed inhibitory effects. Conclusion DKP effectively improved symptoms in rats with dehydroepiandrosterone-induced PCOS. The mechanism of DKP in the treatment of PCOS is related to the CYP17A1 enzyme required for androgen synthesis.
研究领域:
药理学
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中医
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妇科
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代谢组学
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网络药理学
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高影响因子
Journal of Animal Science and Biotechnology
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2022
·Vol. 13
·期 1
·1-13
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IF 6.175
Zhou Xiaoge,Mo Zhaoyi,Li Yankun,Huang Liang,Yu Sihai,Ge Lan,Hu Yamei,Shi Shengjie,Zhang Lutong,Wang Liguang,Gao Lei,Yang Gongshe,Chu Guiyan
Background Oleic acid is an abundant free fatty acid present in livestock that are in a negative energy-balance state, and it may have detrimental effects on female reproduction and fertility. Oleic acid induces lipid accumulation in bovine granulosa cells, which leads to a foam cell-like morphology and reduced steroidogenesis. However, why oleic acid increases lipid accumulation but decreases steroidogenesis remains unclear. This study focused on oleic acid’s effects on lipid type and steroidogenesis. Results Oleic acid increased the lipid accumulation in a concentration-dependent manner and mainly increased the triglyceride level and decreased the cholesterol ester level. Oleic acid also led to a decline in estradiol and progesterone production in porcine granulosa cells in vitro. In addition, oleic acid up-regulated the expression of CD36 and diacylglycerol acyltransferase 2, but down-regulated the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, scavenger receptor class B member 1 and acetyl-Coenzyme A acetyltransferase 2, as well as steroidogenesis-related genes, including cytochrome P450 family 11 subfamily A member 1, cytochrome P450 family 19 subfamily A member 1 and 3 as well as steroidogenic acute regulatory protein at the mRNA and protein levels. An oleic acid-rich diet also enhanced the triglyceride levels and reduced the cholesterol levels in ovarian tissues of female mice, which resulted in lower estradiol levels than in control-fed mice. Compared with the control, decreases in estrus days and the numbers of antral follicles and corpora lutea, as well as an increase in the numbers of the atretic follicles, were found in the oleic acid-fed female mice. Conclusions Oleic acid changed the lipid type stored in lipid droplets of ovarian granulosa cells, and led to a decrease in steroidogenesis. These results improve our understanding of fertility decline in livestock that are in a negative energy-balance state.
研究领域:
生殖生物学
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内分泌学
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动物科学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）