Impact of atropisomerism on a non-steroidal glucocorticoid receptor agonist†

IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics

MedChemComm Pub Date : 2024-05-31 DOI:10.1039/D4MD00245H

Zhou Xu, Zhongyuan Wang, Xiaona Shi, Rui Ding, Li Han, Xueping Yang, Hongmei Zhang and Adrian D. Hobson

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Abstract

To investigate atropisomers of non-steroidal glucocorticoid receptor modulator GSK866, a virtual library of substituted benzoic acid analogues was enumerated. Compounds from this library were subjected to a torsion angle scan using Spartan'20 to calculate the torsion rotation energy barrier which identified compounds predicted to be stable as atropisomers. After synthesis of the library, analysis showed that compounds 13 and 14 existed as stable atropisomers 13a, 13b, 14a and 14b, in agreement with the earlier calculations. Screening in a glucocorticoid receptor cellular assay showed that one compound from each atropisomer pair was significantly more potent than the other. Docking in a public structure of the glucocorticoid receptor (PBD code 3E7C) enabled the stereochemistry of the two most potent compounds 13a and 14b to be assigned as (R_a) and (S_a), respectively.

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阿托品异构对一种非甾体糖皮质激素受体激动剂的影响

为了研究非甾体糖皮质激素受体调节剂 GSK866 的异构体，我们列举了一个取代苯甲酸类似物虚拟库。利用 Spartan'20 对该库中的化合物进行扭转角扫描，计算扭转旋转能垒，从而确定了预测为稳定的异构体化合物。在合成文库后，分析表明化合物 13 和 14 以稳定的异构体 13a、13b、14a 和 14b 的形式存在，与之前的计算结果一致。在糖皮质激素受体细胞试验中进行的筛选表明，每对异构体中的一种化合物的药效明显高于另一种。在糖皮质激素受体的公开结构（PBD 代码 3E7C）中进行对接，可将两种药效最强的化合物 13a 和 14b 的立体化学性质分别定为 (Ra) 和 (Sa)。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

MedChemComm BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL

CiteScore

4.70

自引率

0.00%

发文量

审稿时长

2.2 months

期刊介绍： Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry. In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.