Multi-scale in-silico modelling to unveil structural requirements for DNA-PK inhibitors as radiosensitizers and MolSHAP based design of novel ligands.

Radiosensitizers are agents that make tumour cells more sensitive to radiation therapy. One key mechanism involves inhibition of the DNA-dependent protein kinase (DNA-PK), an enzyme crucial for repairing DNA double-strand breaks in mammalian cells. Suppression of the DNA-PK enzyme compromises the double-strand break repairs to amplify the radiation induced toxicity among the tumour cells. In this study, 73 6‑Anilino Imidazo[4,5‑c]pyridin-2-one derivatives were curated as potent DNA-PK inhibitors and subjected them to 2D -and 3D-Quantitative Structure Activity Relationship analyses to explore their structural requirements. Apart from conventional methodology, we implemented newly developed MolSHAP analyses for R-group analyses. Significant information regarding structural requirements were retrieved from each of these cheminformatic analyses. Additionally, to understand the interaction between the ligands and the DNA-PK receptor, molecular dynamics (MD) simulation analysis of 100 ns were carried out for the most and the least potent compounds among the dataset. The findings indicated H-bond and π-π interactions to be the key factors for binding interactions. Furthermore, novel ligands were designed through the MolSHAP tool and were validated through the chemometric model developed in this investigation. The designed compound exhibited favourable predicted activity and replicated key interaction profiles of the co-crystallized bound ligand in MD simulations. The investigation was carried out through open-access tools to safeguard reproducibility and accessibility among researchers.