3D‐QSAR and Docking Studies of Quinazoline Derivatives with the Inhibitory Activity Toward NF‐κB

Abstract

Nuclear Factor-kB (NF-kB) 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-kB. 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 1 of p50 show a significant correlation between the energy scores and the corresponding experimental values with the correlation coefficient R ¼ 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-kB-DNA binding inhibiting mechanism for these compounds, which prevent free NF-kB 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.

TNF-αRegulates Natriuretic Peptides and Aquaporins in Human Bronchial Epithelial Cells BEAS-2B

“…To further investigate the role of NF- κ B in the modulation of BNP and NPR-1 in BEAS-2B cells after TNF- α treatment, we employed the NF- κ B-DNA binding inhibitor QNZ, which prevents free NF- κ B from binding to DNA [34]. The results obtained with such additional inhibitor, confirmed the previous findings obtained with BAY 11-7082.…”

“…Western blot analysis for the Ser 32 -phosphorylated I κ B- α protein proved the biochemistry evidence of the inhibitory action of BAY 11-7082 on NF- κ B activity ( Figure 3(g) ). To further investigate the role of NF- κ B in the modulation of BNP and NPR-1 in BEAS-2B cells after TNF- α treatment, we employed the NF- κ B-DNA binding inhibitor QNZ, which prevents free NF- κ B from binding to DNA [ 34 ]. The results obtained with such additional inhibitor, confirmed the previous findings obtained with BAY 11-7082.…”

Design, Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives as Anti‐inflammatory Agents against Lipopolysaccharide‐induced Acute Lung Injury in Rats

“…Additionally, different known anti‐inflammatory drugs such as proquazone, fluoroquazone, and tryptanthrin are bearing quinazolinone nucleus (Figure ). Also, it has been reported that some quinazoline derivatives possess potent anti‐inflammatory activity, especially inhibit NF‐κB transcriptional activation . Yet the relationship between anti‐inflammatory activity and structure of quinazoline remains uncertain.…”

Binding Orientations, QSAR, and Molecular Design of Thiophene Derivative Inhibitors

“…Nowadays, comparative molecular field analysis (CoMFA) is a useful technique in understanding the pharmacological properties of studied compounds, because not only CoMFA model is visualized, but also the obtained steric and electrostatic maps may help to understanding the detailed 3D structure of active site of receptor (9–11). Docking analysis is also a useful methodology to further study the action mechanism, as it can offer vivid interaction picture between a ligand and a receptor (12,13).…”