3D-QSAR studies on a series of inhibitors docked into a new homology model of the DNA-PK receptor.

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, 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.

journal_name

Curr Pharm Des

authors

Cao R,Zeng H,Zhang H

doi

10.2174/138161209789649484

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

3796-825

issue

32

eissn

1381-6128

issn

1873-4286

journal_volume

15

pub_type

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