Xyloketal B, a marine compound, acts on a network of molecular proteins and regulates the activity and expression of rat cytochrome P450 3a: a bioinformatic and animal study

Su, Junhui; Chang, Cui; Xiang, Qi; Zhou, Zhi-Wei; Luo, Rong; Yang, Lun; He, Zhi-Xu; Yang, Hongtu; Li, Jianan; Bei, Yu; Xu, Jinmei; Zhang, Minjing; Zhang, Qihao; Su, Zhijian; Huang, Yadong; Pang, Jiyan; Zhou, Shu-Feng

ions, phospholipids, and factor vIIIa. CDOCKER interaction energy ranged from 25 to 46 kcal/mol between CYP3A4 and XKB, midazolam, ketoconazole, and probucol. XKB formed a hydrogen bond with Gly481 at the active site of human CYP3A4 (PDB ID 4K9W; Figure 2A ). Both midazolam and ketoconazole bound to the active site of human CYP3A4 via π-π stacking with Phe108 ( Figure 2B ) and Arg105 (Figure 2C ), respectively. However, probucol did not show hydrogen bond formation, π-π stacking, or charge interaction with human CYP3A4 ( Figure 2D ). Further, we built a homology model of rat Cyp3a2 based on the crystal structure of human CYP3A4 (PDB ID 4K9W). The sequence similarity and identity between the human CYP3A4 and rat Cyp3a2 homology model was 83.3% and 68.4%, respectively. The CDOCKER interaction energy ranged from 23 to 34 kcal/mol ( Table 5 ). The docking results showed that XKB bound to the active site of rat Cyp3a2 homology model by hydrogen bond formation with Ala482 ( Figure 3A) . Midazolam was readily docked into the active site of the rat Cyp3a2 homology model by π-π stacking with Phe305 ( Figure 3B ). Ketoconazole bound with Arg105 by hydrogen bond formation at the active site of the rat Cyp3a2 homology model ( Figure 3C ). However, there was no hydrogen bond formation, π-π stacking, or charge interaction between probucol and the rat Cyp3a2 homology model ( Figure 3D ). The compound-CYP complexes with the highest CDOCKER interaction energy were selected, and two-dimensional and three-dimensional images were taken (Figures 2 and 3) .