Dr. B.C. Roy College of Pharmacy & Allied Health Sciences, Durgapur, 713206, India.
Dr. B.C. Roy College of Pharmacy & Allied Health Sciences, Durgapur, 713206, India; LAQV@REQUIMTE/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007, Porto, Portugal.
Comput Biol Med. 2023 May;157:106789. doi: 10.1016/j.compbiomed.2023.106789. Epub 2023 Mar 13.
Non-alcoholic fatty liver disease (NAFLD) is a pathological condition which is strongly correlated with fat accumulation in the liver that has become a major health hazard globally. So far, limited treatment options are available for the management of NAFLD and partial agonism of Farnesoid X receptor (FXR) has proven to be one of the most promising strategies for treatment of NAFLD. In present work, a range of validated predictive cheminformatics and molecular modeling studies were performed with a series of 3-benzamidobenzoic acid derivatives in order to recognize their structural requirements for possessing higher potency towards FXR. 2D-QSAR models were able to extract the most significant structural attributes determining the higher activity towards the receptor. Ligand-based pharmacophore model was created with a novel and less-explored open access tool named QPhAR to acquire information regarding important 3D-pharmacophoric features that lead to higher agonistic potential towards the FXR. The alignment of the dataset compounds based on pharmacophore mapping led to 3D-QSAR models that pointed out the most crucial steric and electrostatic influence. Molecular dynamics (MD) simulation performed with the most potent and the least potent derivatives of the current dataset helped us to understand how to link the structural interpretations obtained from 2D-QSAR, 3D-QSAR and pharmacophore models with the involvement of specific amino acid residues in the FXR protein. The current study revealed that hydrogen bond interactions with carboxylate group of the ligands play an important role in the ligand receptor binding but higher stabilization of different helices close to the binding site of FXR (e.g., H5, H6 and H8) through aromatic scaffolds of the ligands should lead to higher activity for these ligands. The present work affords important guidelines towards designing novel FXR partial agonists for new therapeutic options in the management of NAFLD. Moreover, we relied mainly on open-access tools to develop the in-silico models in order to ensure their reproducibility as well as utilization.
非酒精性脂肪性肝病（NAFLD）是一种与肝脏脂肪堆积密切相关的病理状态，已成为全球主要的健康危害。目前，NAFLD 的治疗选择有限，法尼醇 X 受体（FXR）的部分激动剂已被证明是治疗 NAFLD 的最有前途的策略之一。在本工作中，对一系列 3-苯甲酰胺苯甲酸衍生物进行了一系列经过验证的预测化学信息学和分子建模研究，以识别其对 FXR 具有更高效力的结构要求。2D-QSAR 模型能够提取出最显著的结构属性，确定对受体的更高活性。使用一种名为 QPhAR 的新颖且探索较少的开放访问工具创建配体基药效团模型，以获取有关导致对 FXR 更高激动潜力的重要 3D 药效团特征的信息。基于药效团映射对齐数据集化合物导致 3D-QSAR 模型，指出了最关键的空间和静电影响。用当前数据集最有效和最无效的衍生物进行分子动力学（MD）模拟，帮助我们了解如何将从 2D-QSAR、3D-QSAR 和药效团模型获得的结构解释与 FXR 蛋白中特定氨基酸残基的参与联系起来。目前的研究表明，配体与羧基之间的氢键相互作用在配体受体结合中起着重要作用，但通过配体的芳构性支架更稳定地稳定靠近 FXR 结合位点的不同螺旋（例如 H5、H6 和 H8），应该导致这些配体具有更高的活性。目前的工作为设计新型 FXR 部分激动剂提供了重要的指导，以作为管理 NAFLD 的新治疗选择。此外，我们主要依靠开放访问工具来开发计算机模型，以确保其可重复性和可利用性。
