基于虚拟筛选和分子动力学模拟发现新型ULK1抑制剂

Unc-51样自噬激活激酶1（unc-51-like autophagy activating kinase 1，ULK1）作为自噬启动的重要调控因子，是肿瘤治疗的关键靶点之一。首先，以已知ULK1抑制剂为基础构建药效团模型，通过药效团模型筛选、分子对接以及分子力学广义波恩表面积（Molecular Mechanics/Generalized Born Surface Area，MM/GBSA）结合自由能计算等方法，对含有52万多个类药性小分子的数据库进行虚拟筛选，得到具有较高理论亲和力的化合物。随后，50ns的分子动力学模拟验证了蛋白质-配体复合物结合的稳定性，最后10ns的平均结合自由能的计算研究进一步验证了配体的结合能力。结果表明，6个化合物（F5258-0159、F3407-0428、F0529-1100、F0696-3531、F3222-5280、F6525-5596）具有骨架新颖、分子对接分数和结合自由能数值优异及与ULK1的结合状态稳定等特点，可以作为新型潜在的ULK1抑制剂用于肿瘤治疗的研究，也为新型ULK1抑制剂的设计和研发提供新的研究思路。

DiscoveryofNovelULK1InhibitorsBasedonVirtualScreeningandMolecularDynamicsSimulation

Unc-51-like autophagy-activating kinase 1 (ULK1) is a crucial regulator of autophagy initiation and serves as a significant target for tumor therapy. Firstly, the pharmacophore model based on known ULK1 inhibitors was constructed. The methods, such as pharmacophore model screening, molecular docking and Molecular Mechanics/ Generalized Born Surface Area (MM/GBSA) binding free energy calculation, were used to screen approximately 520,000 drug-like small molecules in the database to identify compounds with high theoretical affinity. Subsequently, 50ns molecular dynamics (MD) simulation was performed to validate the binding stability of the protein-ligand complexes and the average binding free energy (BFE) of the last 10 ns was calculated to verify the binding ability of the ligands accurately. The results showed that the 6 compounds (F5258-0159, F3407-0428, F0529-1100, F0696-3531, F3222-5280, F6525-5596) have novel skeletons, excellent molecular docking fraction and binding free energy and stable binding state with ULK1. They can be used as new potential ULK1 inhibitors for the research of tumor therapy, which also provided new research ideas for the design and development of new ULK1 inhibitors.