Ejiohuo Ovinuchi, Bajia Donald, Pawlak Joanna, Szczepankiewicz Aleksandra
Department of Psychiatric Genetics, Poznan University of Medical Sciences, 61-701 Poznan, Poland.
Doctoral School, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland.
Biomedicines. 2024 Nov 30;12(12):2745. doi: 10.3390/biomedicines12122745.
The glucocorticoid receptor (GR) is critical in regulating cortisol production during stress. This makes it a key target for treating conditions associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation, such as mental disorders. This study explores novel ligands beyond mifepristone for their potential to modulate GR with improved efficacy and safety. By investigating these interactions, we seek to identify new pharmacotherapeutic options for stress-related mental illness. The ligands asoprisnil, campestanol, and stellasterol were selected based on structural similarities to mifepristone (reference ligand) and evaluated for pharmacological and ADME (absorption, distribution, metabolism, and excretion) properties using the SwissADME database. Molecular docking with AutoDock 4.2.6 and molecular dynamics simulations were performed to investigate ligand-protein interactions with the human glucocorticoid receptor, and binding free energies were calculated using MMPBSA. Pharmacokinetic analysis revealed that asoprisnil exhibited high gastrointestinal absorption and obeyed Lipinski's rule, while mifepristone crossed the blood-brain barrier. Toxicological predictions showed that mifepristone was active for neurotoxicity and immunotoxicity, while asoprisnil, campestanol, and stellasterol displayed lower toxicity profiles. Asoprisnil demonstrated the highest stability in molecular dynamics simulations, with the highest negative binding energy of -62.35 kcal/mol, when compared to mifepristone, campestanol, and stellasterol, with binding energies of -57.08 kcal/mol, -49.99 kcal/mol, and -46.69 kcal/mol, respectively. This makes asoprisnil a potentially favourable therapeutic candidate compared to mifepristone. However, further validation of asoprisnil's interaction, efficacy, and safety in stress-related mental disorders through experimental studies and clinical trials is needed.
糖皮质激素受体（GR）在应激期间调节皮质醇产生过程中起关键作用。这使其成为治疗与下丘脑 - 垂体 - 肾上腺（HPA）轴失调相关病症（如精神障碍）的关键靶点。本研究探索米非司酮以外的新型配体，以其具有改善疗效和安全性来调节GR的潜力。通过研究这些相互作用，我们试图确定应激相关精神疾病的新药物治疗选择。基于与米非司酮（参考配体）的结构相似性选择了阿索普尼尔、菜子甾醇和海星甾醇等配体，并使用SwissADME数据库评估其药理和ADME（吸收、分布、代谢和排泄）特性。利用AutoDock 4.2.6进行分子对接和分子动力学模拟，以研究配体与人糖皮质激素受体的相互作用，并使用MMPBSA计算结合自由能。药代动力学分析表明，阿索普尼尔具有高胃肠道吸收并符合Lipinski规则，而米非司酮可穿过血脑屏障。毒理学预测显示，米非司酮具有神经毒性和免疫毒性活性，而阿索普尼尔、菜子甾醇和海星甾醇的毒性较低。与米非司酮、菜子甾醇和海星甾醇相比，阿索普尼尔在分子动力学模拟中表现出最高的稳定性，其结合能分别为-57.08 kcal/mol、-49.99 kcal/mol和-46.69 kcal/mol，阿索普尼尔的最高负结合能为-62.35 kcal/mol。与米非司酮相比，这使阿索普尼尔成为潜在有利的治疗候选药物。然而，需要通过实验研究和临床试验进一步验证阿索普尼尔在应激相关精神障碍中的相互作用、疗效和安全性。
