Aromatase and steroidal sulfatase (STS) are steroidogenic enzyme that increases the concentration of estrogens in circulation, a primary factor leading to breast cancer. At molecular level, 87% of STS is expressed and an inhibitor targeting STS could decrease the level of estrogens. In an attempt to identify the chemical structural requirement targeting placental STS inhibition, 26 compounds with pIC50 ranging from 4.61 to 9.46 were subjected to computational studies including Quantitative Structural-Activity Relationship (QSAR), MolecularDocking followed by Density Functional Theory (DFT) studies. A robust and predictable model were developed with good R2 (0.834) and cross-validated correlation coefficient value Q2 LOO (0.786) explaining the relationship quantitatively. The regression graphs suggests that the STS inhibition was greatly dependent on the electro topological state of an atom, sum of the atom type E-state (SdssC), maximum E-states for strong hydrogen bond acceptors (maxHBa) and basic group count descriptor (BCUTp-1h). Furthermore, docking results showed favorable interactions of sulfamate analogs with catalytically important amino acid residues such as LEU74, VAL101, and VAL486. The interactions of the best active compound 3j when compared with standard Irosustat show similar binding energies. DFT studies further confirm the presence of HOMO orbital centered on chromenone ring further highlighting its importance for receptor ligand hydrophobic interaction. The study reveals that substitution of thio in chromenone nucleus and introduction of adamantyl substitution at second position are favorable in inhibiting the enzyme STS.

中文翻译：

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使用 QSAR、分子对接和 DFT 对 4-(硫代)-色酮 6-O-氨基磺酸酯类似物进行先导优化——一种作为甾体硫酸酯酶抑制剂的组合方法

芳香酶和甾体硫酸酯酶 (STS) 是类固醇生成酶，可增加循环中雌激素的浓度，这是导致乳腺癌的主要因素。在分子水平上，87% 的 STS 被表达，靶向 STS 的抑制剂可以降低雌激素的水平。为了确定针对胎盘 STS 抑制的化学结构要求，对 pIC50 范围为 4.61 至 9.46 的 26 种化合物进行了计算研究，包括定量结构活性关系 (QSAR)、分子对接和密度泛函理论 (DFT) 研究。开发了具有良好 R2 (0.834) 和交叉验证相关系数值 Q2 LOO (0.786) 的稳健且可预测的模型，定量地解释了这种关系。回归图表明 STS 抑制在很大程度上取决于原子的电拓扑状态、原子类型 E 状态 (SdssC) 的总和、强氢键受体的最大 E 状态 (maxHBa) 和基本基团计数描述符 ( BCUTp-1h)。此外，对接结果显示氨基磺酸盐类似物与重要的催化氨基酸残基如 LEU74、VAL101 和 VAL486 之间存在良好的相互作用。与标准 Irosustat 相比，最佳活性化合物 3j 的相互作用显示出相似的结合能。DFT 研究进一步证实了以色酮环为中心的 HOMO 轨道的存在，进一步突出了其对受体配体疏水相互作用的重要性。