In-silico screening for DNA-dependent protein kinase (DNA-PK) inhibitors: Combined homology modeling,docking, molecular dynamic study followed by biological investigation |
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| Institution: | 1. College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates;2. Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates;3. Cancer Biology Department, Cairo University, Cairo, Egypt;1. State Civil Servant Hospital (IAMSPE), São Paulo, Brazil;2. Oncology/Hematology Discipline, ABC Medical School, Santo André, São Paulo, Brazil;3. Paulista University, São Paulo, Brazil;4. Institute of Chemical and Pharmaceutical Sciences, UNIFESP, Diadema, São Paulo, Brazil;1. Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, PMB 12003, Idi-araba, Lagos, Nigeria;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Lagos, Lagos, Nigeria;1. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), University of Dammam, Dammam 31441, Saudi Arabia;2. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia;3. Faculty of Applied Science, UiTM, 40450 Shah Alam, Selangor, Malaysia;4. Department of Biochemistry, Abdul Wali Khan University, Mardan, Khyber Pukhtunkhwa, Pakistan;5. Department of Chemistry, College of Sciences and Humanities, Prince Sattam bin Abdulaziz University, P.O. Box 83, Al-Kharij 11942, Saudi Arabia;6. Universiti Kebangsaan Malaysia, School of Chemical Sciences and Food Technology, Bangi, Malaysia;7. Department of Chemistry, Hazara University, Mansehra 21300, Khyber Pukhtunkhwa, Pakistan;8. Department of Chemistry, COMSATS Institute of Information Technology, University Road, Abbottabad 22060, KPK, Pakistan;9. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;1. Laboratory of Natural Medicine Research and Development in Wuling Mountain, School of Chemistry and Chemical Engineering, Yangtze Normal University, Fuling 408100, China;2. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China |
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| 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 IC50 of 17.3 μM for praziquantel and >20 μM 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. |
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| Keywords: | DNA-PK Homology modeling Virtual screening Molecular dynamic |
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