Abstract
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, r2 =0.876; CoMSIA: q2 = 0.503, r2 =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.
Keywords: DNA-PK kinase, homology modeling, molecular dynamics, molecular docking, 3D-QSAR, CoMFA, CoMSIA
Current Pharmaceutical Design
Title: 3D-QSAR Studies on a Series of Inhibitors Docked into a New Homology Model of the DNA-PK Receptor
Volume: 15 Issue: 32
Author(s): Ran Cao, Huahui Zeng and Huabei Zhang
Affiliation:
Keywords: DNA-PK kinase, homology modeling, molecular dynamics, molecular docking, 3D-QSAR, CoMFA, CoMSIA
Abstract: 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, r2 =0.876; CoMSIA: q2 = 0.503, r2 =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.
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Cite this article as:
Cao Ran, Zeng Huahui and Zhang Huabei, 3D-QSAR Studies on a Series of Inhibitors Docked into a New Homology Model of the DNA-PK Receptor, Current Pharmaceutical Design 2009; 15 (32) . https://dx.doi.org/10.2174/138161209789649484
DOI https://dx.doi.org/10.2174/138161209789649484 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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