Liu Sijie, Wu Jie, Chen Ya, Wolf Clemens Alexander, Bureik Matthias, Kirchmair Johannes, Marchisio Mario Andrea, Wolber Gerhard
Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
J Chem Inf Model. 2025 Apr 14;65(7):3529-3543. doi: 10.1021/acs.jcim.5c00204. Epub 2025 Mar 19.
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 , a novel, noncovalent inhibitor based on coumarin and imidazole substructures, stood out by its high potency, with an IC value of 271 ± 51 nM.
人细胞色素P450 19A1（CYP19A1，芳香化酶）是一种含血红素的蛋白质，催化甾体激素17β-雌二醇生物合成的最后步骤。由于其在介导雄激素向雌激素转化中的作用，它是治疗性激素相关疾病的关键靶点。在此，我们报告了一种结合机器学习和基于结构建模的虚拟筛选工作流程的开发，该流程导致发现了新的CYP19A1抑制剂。机器学习模型基于从ChEMBL和PubChem生物测定数据库中提取的综合CYP19A1数据集构建，并经过全面的验证程序。从虚拟筛选活动中产生的10个有前景的命中化合物被选用于基于人CYP19A1在酵母中的异源表达的酶促试验中的实验测试。在被鉴定为新的CYP19A1抑制剂的7种结构多样的化合物中，化合物 ，一种基于香豆素和咪唑亚结构的新型非共价抑制剂，因其高效能而脱颖而出，IC值为271±51 nM。
