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Identification and Validation of New DNA-PKcs Inhibitors through High-Throughput Virtual Screening and Experimental Verification

Authors :
Liujiang Dai
Pengfei Yu
Hongjie Fan
Wei Xia
Yaopeng Zhao
Pengfei Zhang
John Z. H. Zhang
Haiping Zhang
Yang Chen
Source :
International Journal of Molecular Sciences, Vol 25, Iss 14, p 7982 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

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.

Details

Language :
English
ISSN :
14220067 and 16616596
Volume :
25
Issue :
14
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.ba7857cf252048c89dd3c5f6c985aca5
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms25147982