【摘要】 目的 基于分子对接、分子动力学模拟和MM/PBSA自由能计算虚拟筛选技术，从中药中发现抗肺纤维化VEGFR2抑制剂。方法 采用LeDock对接程序对肺纤维化VEGFR2信号受体蛋白的多个共晶结构进行虚拟筛选方法学研究，发现1Y6B共晶结构对活性分子富集能力较强，利用此模型从中药系统药理学数据库与分析平台TCMSP中筛选出与VEGFR2蛋白结合能力较强，且符合类药性规则的5个活性化合物。结果 结合亲和力数据表明两个候选化合物MOL006504和MOL007136与受体蛋白有较强的相互作用。分子动力学模拟显示，两个化合物与蛋白受体均能稳定结合。MM/PBSA结合自由能计算显示，候选化合物与受体的结合自由能均与原配体相近，主要作用方式为范德华力、静电作用和表面溶剂化作用。结论 通过分子对接、分子动力学模拟及MM/PBSA自由能计算等技术，筛选得到两个化合物MOL006504和MOL007136,可与靶蛋白(VEGFR2)稳定结合，结合构象稳定性及能量特征分析结果表明，两个化合物展现出良好的VEGFR2抑制活性，为开发高效、低毒的抗肺纤维化药物提供了有益的探索与思路。更多还原

【Abstract】 Focusing on interstitial lung disease associated with rheumatoid arthritis, we employed virtual screening techniques including molecular docking, molecular dynamics simulation, and MM/PBSA free energy calculations to discover VEGFR2 inhibitors from traditional Chinese medicine with potential anti-pulmonary fibrosis effects.Using the LeDock docking program, we conducted methodological validation based on multiple co-crystal structures of the VEGFR2 signaling receptor protein relevant to pulmonary fibrosis.The 1Y6B co-crystal structure was identified as having superior enrichment capability for active molecules.Using this model, five active compounds were virtually screened from the Traditional Chinese Medicine Systems Pharmacology(TCMSP) database which exhibit strong binding ability to VEGFR2 and conform to Lipinski rules.Binding affinity data revealed that the two candidate compounds, MOL006504 and MOL007136,showed substantial interactions with the receptor protein.Molecular dynamics simulations indicated that both compounds can stably bind to the protein receptor.To further validate their inhibitory activity, MM/PBSA binding free energy calculations were performed.The results showed that the binding free energies of the candidate compounds were comparable to those of the original ligand.The primary interactions involved Van der Waals force, electrostatic force, and solvation effect.These findings suggest that both compounds can strongly interact with VEGFR2 and may exhibit promising inhibitory activity against this target in the context of pulmonary fibrosis.This study provides a valuable foundation for the development of highly effective and low-toxicity anti-pulmonary fibrosis drugs.更多还原