In-silico screening for DNA-dependent protein kinase (DNA-PK) inhibitors: Combined homology modeling, docking, molecular dynamic study followed by biological investigation.

• 影响指数: 7.419
• 发表时间: Oct 2016
• 来源期刊: Biomed Pharmacother
• DOI: 10.1016/j.biopha.2016.07.044
• PMID: 27470570
• 文章类型: Journal Article
• 中科院分区: Q2
• 方向: 医学
• 作者列表: Tarazi H,Saleh E,El-Awady R

关键词: DNA-PK; Homology modeling; Molecular dynamic; Virtual screening

Mesh: Antineoplastic Agents / chemistry pharmacology; Catalytic Domain; Computer Simulation; DNA-Activated Protein Kinase / antagonists & inhibitors chemistry metabolism; Drug Evaluation, Preclinical; Dutasteride / chemistry pharmacology; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Praziquantel / chemistry pharmacology; Protein Kinase Inhibitors / analysis chemistry pharmacology; ROC Curve; Structural Homology, Protein

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 17.3μM 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.