Elgharbaoui Boutaina, Bouricha E L Mehdi, El Guenouni Kaoutar, Magri Meryam, Belyamani Lahcen, Ibrahimi Azeddine, ELjaoudi Rachid, Elhafidi Naima
Medical Biotechnology Laboratory (MedBiotech), Faculty of Medecine and Pharmacy of Rabat, Mohammed Vth University in Rabat, Rabat, Morocco.
Mohammed VI University of Sciences and Health, UM6SS, Casablanca, Morocco.
Mol Divers. 2025 Sep 5. doi: 10.1007/s11030-025-11336-x.
Asthma is a chronic inflammatory disorder of the airways. Standard treatments, such as inhaled corticosteroids like fluticasone, beclomethasone, and budesonide, are effective in managing asthma symptoms by reducing inflammation through immune suppression. However, prolonged corticosteroid therapy can impair vitamin D metabolism, exacerbating vitamin D deficiency, which is essential for immune regulation and anti-inflammatory responses via the vitamin D receptor (VDR). Activation of the pregnane X receptor (PXR) by corticosteroids induces cytochrome P450 enzyme CYP24A1, accelerating vitamin D catabolism and reducing its anti-inflammatory efficacy. This effect is mediated through the interaction between PXR and its nuclear partner, the retinoid X receptor (RXR), which together regulate gene transcription. Disrupting this PXR-RXR dimerization could offer a selective means to prevent vitamin D degradation without interfering with other physiological functions of PXR or RXR.In this study, we aimed to inhibit the PXR and retinoid X receptor (RXR) interaction by designing peptidomimetic molecules based on the key RXR residues interacting with PXR. To achieve this, we used a multifaceted approach, incorporating pharmacophore and similarity-based peptidomimetics screening, molecular docking, ADMET analysis, and molecular dynamics (MD) simulations. The molecular docking results indicated that 38 compounds had a docking score higher than - 7. Among them, six showed favorable ADMET properties. These molecules were then subjected to MD simulations, where two molecules, notably MMs02510246 and MMs03733211, showed strong interaction with PXR during the 300 ns of MD simulation. Two others partially changed the starting binding site, while two others completely retained their initial binding site and bound to another site. Our study identified two potential molecules that could inhibit the PXR-RXR interaction. These two molecules could potentially inhibit the PXR-RXR interaction, which may help reduce corticosteroid-induced vitamin D inactivation, thereby improving asthma management outcomes without compromising vitamin D's anti-inflammatory benefits. Further experimental analyses are needed to validate our results.
哮喘是一种气道慢性炎症性疾病。标准治疗方法，如吸入氟替卡松、倍氯米松和布地奈德等皮质类固醇，通过免疫抑制减轻炎症，从而有效控制哮喘症状。然而，长期使用皮质类固醇治疗会损害维生素D代谢，加剧维生素D缺乏，而维生素D通过维生素D受体（VDR）对免疫调节和抗炎反应至关重要。皮质类固醇激活孕烷X受体（PXR）会诱导细胞色素P450酶CYP24A1，加速维生素D分解代谢并降低其抗炎功效。这种作用是通过PXR与其核伴侣视黄酸X受体（RXR）之间的相互作用介导的，它们共同调节基因转录。破坏这种PXR-RXR二聚化可能提供一种选择性方法来防止维生素D降解，而不干扰PXR或RXR的其他生理功能。在本研究中，我们旨在通过基于与PXR相互作用的关键RXR残基设计拟肽分子来抑制PXR和视黄酸X受体（RXR）的相互作用。为实现这一目标，我们采用了多方面的方法，包括药效团和基于相似性的拟肽筛选、分子对接、ADMET分析和分子动力学（MD）模拟。分子对接结果表明，38种化合物的对接分数高于-7。其中六种具有良好的ADMET性质。然后对这些分子进行MD模拟，其中两个分子，特别是MMs02510246和MMs03733211，在300 ns的MD模拟过程中与PXR表现出强烈相互作用。另外两个分子部分改变了起始结合位点，而另外两个分子完全保留了其初始结合位点并与另一个位点结合。我们的研究确定了两种可能抑制PXR-RXR相互作用的潜在分子。这两种分子可能抑制PXR-RXR相互作用，这可能有助于减少皮质类固醇诱导的维生素D失活，从而在不损害维生素D抗炎益处的情况下改善哮喘管理效果。需要进一步的实验分析来验证我们的结果。
