title: In-silico screening for DNA-dependent protein kinase (DNA-PK) inhibitors: Combined homology modeling, docking, molecular dynamic study followed by biological investigation.
abstract: 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 IC50of 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.
authors.affiliation: College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates. Electronic address: htarazi@sharjah.ac.ae.
authors.forename: Hamadeh
authors.initials: H
authors.lastname: Tarazi
authors.affiliation: Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; Cancer Biology Department, Cairo University, Cairo, Egypt.
authors.forename: Ekram
authors.initials: E
authors.lastname: Saleh
authors.affiliation: College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.
authors.forename: Raafat
authors.initials: R
authors.lastname: El-Awady
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D000068538:Dutasteride / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011223:Praziquantel / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry* / Q000494:pharmacology; D012372:ROC Curve; D040681:Structural Homology, Protein
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011223:Praziquantel; D051747:DNA-Activated Protein Kinase; D000068538:Dutasteride
keywords: DNA-PK; Homology modeling; Molecular dynamic; Virtual screening