3D-QSAR and docking studies of quinazoline derivatives with the inhibitory activity toward NF-kappa B

作者：Qian Li; Shen Yong; Chen Jin Can; Wang Ya Xue; Wu Xiao Tian; Chen Tao Ju; Zheng Kang Cheng^*

来源：QSAR and Combinatorial Science, 2008, 27(8): 984-995.

DOI：10.1002/qsai.200710132

Nuclear Factor-kappa B (NF-kappa B) is an important transcription factor for regulation expression of many cytokines that are involved in the pathogenesis of inflammatory diseases such as Adult Respiratory Distress Syndrome (ARDS). sepsis syndrome. and HIV. It is recently proposed that quinazoline derivatives are capable of inhibiting the activation of NF-kappa B. To study the inhibiting mechanism and obtain some helpful information for designing functional inhibitor against the protein, 3-D Quantitative Structure-Activity Relationship (3D-QSAR) studies such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) and docking analysis on 29 inhibitors, quinazoline derivatives, have been carried out. The CoMFA and CoMSIA models give a cross-validated coefficient q(2) of 0.822 and 0.801, respectively. The binding pockets around the DNA binding sites in p50 and p65 have been tested for docking. The docking results at site I of p50 show a significant correlation between the energy scores and the corresponding experimental values with the correlation coefficient R=0.817. The contour maps of 3D-QSAR model are shown in a good agreement with the structural characteristics of the corresponding binding site. These results indicate a NF-kappa B-DNA binding inhibiting mechanism for these compounds, which prevent free NF-kappa B from binding to DNA. Therefore, the final 3D-QSAR models and the information of the binding site would be useful in developing new quinazoline derivatives with favorable activity.

• 出版日期2008-8
• 单位中山大学