Yang Li-Ping, Zhou Zhi-Wei, Chen Xiao-Wu, Li Chun Guang, Sneed Kevin B, Liang Jun, Zhou Shu-Feng
School of Health Sciences & Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia.
Xenobiotica. 2012 Mar;42(3):238-55. doi: 10.3109/00498254.2011.610833. Epub 2011 Oct 4.
Human CYP1A2 is an important enzyme for drug metabolism and procarcinogen activation. This study aimed to explore the binding mode of ligands with CYP1A2 and to screen potential inhibitors from a library of herbal compounds using computational and in vitro approaches. The heme prosthetic group and six residues (Thr124, Phe125, Phe226, Phe260, Gly316, and Ala317) in the active site of CYP1A2 were identified as important residues for ligand binding using the LIGPLOT program. Ala317 in helix I immediately above heme was highly conserved in most human CYPs with known crystal structures. In molecular docking, 19 of the 56 herbal compounds examined were identified as potential inhibitors of CYP1A2. Up to 21 of the 56 herbal compounds were hit by the pharmacophore model of CYP1A2 inhibitors developed and validated in this study. In the in vitro inhibition study, 8 herbal compounds were identified as moderate to potent inhibitors of CYP1A2. Five of the 8 herbal compounds predicted to be potential inhibitors were confirmed as CYP1A2 inhibitors in the in vitro study. A combination of computational and in vitro approaches, represent a useful tool to identify potential inhibitors for CYP1A2 from herbal compounds.
人细胞色素P450 1A2（CYP1A2）是药物代谢和前致癌物激活的重要酶。本研究旨在利用计算方法和体外实验方法探索配体与CYP1A2的结合模式，并从草药化合物库中筛选潜在抑制剂。使用LIGPLOT程序确定CYP1A2活性位点中的血红素辅基和六个残基（Thr124、Phe125、Phe226、Phe260、Gly316和Ala317）是配体结合的重要残基。在血红素上方的螺旋I中的Ala317在大多数具有已知晶体结构的人细胞色素P450中高度保守。在分子对接中，所检测的56种草药化合物中有19种被鉴定为CYP1A2的潜在抑制剂。本研究开发并验证的CYP1A2抑制剂药效团模型命中了56种草药化合物中的多达21种。在体外抑制研究中，8种草药化合物被鉴定为CYP1A2的中度至强效抑制剂。预测为潜在抑制剂的8种草药化合物中有5种在体外研究中被确认为CYP1A2抑制剂。计算方法和体外实验方法相结合，是从草药化合物中鉴定CYP1A2潜在抑制剂的有用工具。
