| 周新宇,李静静,杨铠银,闫红,高学云.化学通报,2025,88(12):1325-1332. |
| 新型谷氨酰胺酰基环化酶抑制剂的虚拟筛选与分子动力学模拟研究 |
| Virtual Screening and Molecular Dynamics Simulations of Novel QC Inhibitors |
| 投稿时间：2025-07-03 修订日期：2025-08-25 |
| DOI： |
| 中文关键词: QC抑制剂 阿尔茨海默病 虚拟筛选 分子动力学模拟 |
| 英文关键词:QC inhibitors, Alzheimer"s disease, Virtual screening, Molecular dynamics simulations |
| 基金项目:河北省自然科学基金项目(H2024209021)资助 |
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| 中文摘要: |
| 谷氨酰胺酰基环化酶(Glutaminyl cyclase, QC)催化生成的焦谷氨酸修饰β-淀粉样蛋白(pyroglutamylated β-amyloid, pE-Aβ),是加速阿尔茨海默病(Alzheimer’s Disease, AD)的关键因素之一。QC抑制剂的设计与开发已成为抗AD药物研发的重要策略之一。本研究采用基于结构的虚拟筛选(structure-based virtual screening, SBVS)策略,对Topscience数据库中的2000余万种小分子依次进行高通量虚拟筛选(high-throughput virtual screening, HTVS)、标准精度(standard precision, SP)和超精度(extra precision, XP)三个层次的分子对接研究,最终获得6个具有高理论亲和力的候选化合物(P348, P033, P200, P992, P704和P925),并对它们的吸收、分布、代谢、排泄和毒性(ADMET)性质进行了评价分析。通过200 ns分子动力学模拟验证了候选化合物与QC复合物体系的稳定性。结合分子力学/泊松-玻尔兹曼表面积(MM/PBSA)方法计算平均结合自由能,进一步评估了候选化合物在动态溶剂化环境下与QC蛋白的亲和力。结果表明,6个候选化合物与QC蛋白形成的复合体系均保持良好的稳定性,且其亲和力均强于参考化合物PBD150。这表明6个候选化合物可作为新型QC抑制剂,并为后续结构优化及生物活性研究提供了理论指导。 |
| 英文摘要: |
| Glutaminyl cyclase (QC) catalyzes the formation of pyroglutamylated β-amyloid (pE-Aβ), playing a pivotal role in the progression of Alzheimer"s disease (AD). Therefore, the design and development of QC inhibitors have become an important strategy in the research and development of anti-AD drug. This study adopts the structure-based virtual screening (SBVS) strategy on the Topscience database containing over 20 million small molecules to identified the novel QC inhibitor. The sequential molecular docking at three levels of precision, high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) were conducted, and six candidate compounds (P348, P033, P200, P992, P704, P925) were identified as QC inhibitors with high theoretical binding affinity. Their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were evaluated. The stability of the candidate compound with QC protein complexes was assessed through 200 ns molecular dynamics (MD) simulations, and the binding affinity of the complexes under dynamic solvation conditions was calculated by using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. The results demonstrated that all six candidate compounds can form stable complexes with the QC protein and exhibited stronger binding affinity than those of reference PBD150. These findings suggested that the candidate compounds can be used as novel QC inhibitors and provided a theoretical guidance for further structural optimization and biological activity investigations. |
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