In-silico screening for DNA-dependent protein kinase (DNA-PK) inhibitors: Combined homology modeling, docking, molecular dynamic study followed by biological investigation.
DNA-dependent protein kinase (DNA-PK) is a key enzyme in non-homologous DNA end joining (NHEJ) repair pathway. The targeted inhibition of such enzyme would furnish a valuable option for cancer treatment. In this study we report the development of validation of enzyme homology model, and the subsequent use of this model to perform docking-based virtual screening against a database of FDA-approved drugs. The nominated highest ranking hits (Praziquantel and Dutasteride) were subjected to biological investigation. Additionally, molecular dynamic study was carried-out for binding mode exploration. Results of the biological evaluation revealed that both compounds inhibit the DNA-PK enzymatic activity at relatively high concentration levels with an IC50 of 17.3μM for praziquantel and >20μM for dutasteride. Furthermore, both agents enhanced the anti-proliferative effects of doxorubicin and cisplatin on breast cancer (MCF7) and lung cancer (A549) cell lines. This result indicates that these two hits are good candidate as DNA-PK inhibitors and worth further structural modifications to enhance their enzyme inhibitory effects.
['Tarazi|Hamadeh|H|', 'Saleh|Ekram|E|', 'El-Awady|Raafat|R|']
D000970:Antineoplastic Agents D020134:Catalytic Domain D003198:Computer Simulation D051747:DNA-Activated Protein Kinase D004353:Drug Evaluation, Preclinical D000068538:Dutasteride D006801:Humans D008024:Ligands D062105:Molecular Docking Simulation D056004:Molecular Dynamics Simulation D011223:Praziquantel D047428:Protein Kinase Inhibitors D012372:ROC Curve D040681:Structural Homology, Protein
DNA-PK Homology modeling Molecular dynamic Virtual screening