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