3D-QSAR studies on a series of inhibitors docked into a new homology model of the DNA-PK receptor.
Cancer therapies through ionizing radiation or chemotherapeutic treatment may result in DNA double strand breaks (DSBs) in cell. DNA-PK has emerged as an attractive target for drug discovery efforts toward DSBs repair and in V(D)J recombination. Hence, the search for potent and selective DNA-PK inhibitors has received particular attention and several series of activity inhibitors have been reported. In this article, we gave a report of the DNA-PK activation and the corresponding inhibitors, which belong to different chemical classes. Then homology modeling and molecular dynamics (MD) simulation were used to build the 3D model of DNA-PK receptor based on the X-ray structure of PI3K. All of the ligands were docked into the putative binding site of the 3D model of DNA-PK using the flexible docking method, and the probable interaction model between DNA-PK and the ligands were obtained. Based on the docking conformations and their alignment inside the binding pocket of DNA-PK, 3D QSAR analyses were performed on 259 ligands using CoMFA and CoMSIA methods. Both CoMFA and CoMSIA provide statistically valid models with good correlation and predictive power (CoMFA: q2 = 0.563, r(2) =0.876; CoMSIA: q(2) = 0.503, r(2) =0.870). Our models would offer help to better comprehend the structure-activity relationship existent for this class of compounds and also facilitate the design of new inhibitors with good chemical derivsity.
Cao
Ran
R
Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
Zeng
Huahui
H
Zhang
Huabei
H
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001665:Binding Sites; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D021281:Quantitative Structure-Activity Relationship; D011832:Radiation Injuries
D000970:Antineoplastic Agents; D008024:Ligands; D051747:DNA-Activated Protein Kinase