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目的 利用计算机辅助药物设计技术挖掘拮抗细胞毒性胆汁酸的中药单体成分抑制剂。方法 使用三维定量构效关系(3D-QSAR)学习34个已有的法尼醇受体(FXR)抑制剂的药效团特征，建立机器预测模型，搭配药代动力学预测(ADMET)来虚拟筛选13 144个中药单体，得到候选化合物。随后，以分子对接和分子动力学模拟为方法，模拟候选化合物、FXR激动剂鹅去氧胆酸(CDCA)、FXR抑制剂(Z)-Gugglesterone对FXR配体结构域的竞争性结合，以及对转录复合物结构稳定性的影响。结果2 436个中药单体通过了机器预测筛选，具备FXR抑制剂药效团特征；随后选取IC50预测值位于前300名(IC50 < 0.286 nM)的单体进行ADMET预测，最终苦参啶被虚拟筛选为候选化合物，ADMET结果表明，苦参啶具有良好的类药性、口服吸收能力和低毒性。分子对接和动力学模拟结果显示，苦参啶能以更强力的方式和CDCA、(Z)-Gugglesterone竞争FXR的相同结合位点，强力减弱FXR和共激活因子之间的结合。结论 苦参啶有潜力成为强效FXR抑制剂的先导化合物，该研究结合了基于配体和结构的计算机辅助药物设计，为进一步的实验验证提供理论依据。
Abstract：Objective To discover herbal monomer-based inhibitors of cytotoxic bile acids via computer-aided drug design.Methods 3D quantitative structure-activity relationship (3D-QSAR) modeling was used to analyze the pharmacophore features of 34 known FXR inhibitors and establish machine predictive models.The model achieving optimal predictive performance,combined with pharmacokinetic prediction (ADMET),was utilized to virtually screen 13 144 herbal monomeric compounds for candidate identification.Molecular docking and molecular dynamics simulations were performed to evaluate the competitive binding of candidate compounds,the FXR agonist chenodeoxycholic acid (CDCA),and the FXR inhibitor (Z)-Guggulsterone to the FXR ligand-binding domain(FXR-LBD),as well as their effects on the structural stability of the transcription complex.Results A total of 2 436 herbal monomers passed the pharmacophore model screening,exhibiting FXR inhibitor pharmacophore characteristics.The top 300 monomers with estimated IC50 values (IC50 < 0.286 nM) were subjected to ADMET prediction,leading to the virtual identification of kuraridin as the candidate compound.ADMET results indicated that kuraridin possesses favorable drug-likeness,oral absorption and low toxicity.Molecular docking and dynamics simulation results showed that kuraridin could compete for the same binding site on FXR-LBD with CDCA and (Z)-Gugglesterone in a more potent binding energy,strongly weakening the binding between FXR and co-activators and thus reducing the structural stability of the transcription complex.Conclusion Kuraridin has the potential to be a potent FXR inhibitor and serve as a lead compound.This study combines ligand-based and structure-based computer-aided drug design,providing a theoretical basis for further experimental validation.
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基本信息:
DOI：10.13728/j.1673-6427.2025.04.006
中图分类号:TP391.72;R284
引用信息:
[1]黄圣,冯丽娜,林茂炫等.基于计算机辅助药物设计筛选中药单体中的法尼醇受体抑制剂[J].现代中药研究与实践,2025,39(04):35-43.DOI:10.13728/j.1673-6427.2025.04.006.
基金信息:
内蒙古自治区卫生健康委员会公立医院科研联合基金科技项目(2024GLLH1364)