PDF(Pubmed)
Abstract：
DNA-PKcs is a crucial protein target involved in DNA repair and response pathways, with its abnormal activity closely associated with the occurrence and progression of various cancers. In this study, we employed a deep learning-based screening and molecular dynamics (MD) simulation-based pipeline, identifying eight candidates for DNA-PKcs targets. Subsequent experiments revealed the effective inhibition of DNA-PKcs-mediated cell proliferation by three small molecules (5025-0002, M769-1095, and V008-1080). These molecules exhibited anticancer activity with IC50 (inhibitory concentration at 50%) values of 152.6 μM, 30.71 μM, and 74.84 μM, respectively. Notably, V008-1080 enhanced homology-directed repair (HDR) mediated by CRISPR/Cas9 while inhibiting non-homologous end joining (NHEJ) efficiency. Further investigations into the structure-activity relationships unveiled the binding sites and critical interactions between these small molecules and DNA-PKcs. This is the first application of DeepBindGCN_RG in a real drug screening task, and the successful discovery of a novel DNA-PKcs inhibitor demonstrates its efficiency as a core component in the screening pipeline. Moreover, this study provides important insights for exploring novel anticancer therapeutics and advancing the development of gene editing techniques by targeting DNA-PKcs.
摘要：
DNA-PKcs是参与DNA修复和反应途径的关键蛋白质靶标，其异常活性与各种癌症的发生和进展密切相关。在这项研究中,我们采用了基于深度学习的筛选和基于分子动力学(MD)模拟的管道，确定八个候选DNA-PKcs目标。随后的实验揭示了三种小分子(5025-0002、M769-1095和V008-1080)对DNA-PKcs介导的细胞增殖的有效抑制。这些分子表现出抗癌活性，IC50（抑制浓度为50％）值为152.6μM，30.71μM,和74.84μM，分别。值得注意的是,V008-1080增强由CRISPR/Cas9介导的同源定向修复(HDR),同时抑制非同源末端连接(NHEJ)效率。对结构-活性关系的进一步研究揭示了这些小分子与DNA-PKcs之间的结合位点和关键相互作用。这是DeepBindGCN_RG在实际药物筛选任务中的初次运用，一种新型DNA-PKcs抑制剂的成功发现证明了其作为筛选流程中核心成分的有效性。此外，这项研究为探索新的抗癌疗法和通过靶向DNA-PKcs推进基因编辑技术的发展提供了重要的见解。
