Inhibition of cytochrome p450 enzymes by quinones and anthraquinones.
Inhibition of cytochrome p450 enzymes by quinones and anthraquinones.
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DOI：
10.1021/tx2004163
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发表时间：
2012-02-20
影响因子：
4.1
通讯作者：
Klein Stevens CL
中科院分区：
文献类型：
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作者：
Sridhar J;Liu J;Foroozesh M;Klein Stevens CL
对一些细胞色素P450抑制剂的硅对接研究和定量结构-活性关系分析已经揭示了一个分子作为P450酶1A1, 1A2, 2B1和/或2A6的良好抑制剂所需的重要结构特征。这些见解被纳入用于中医药数据库二维搜索的药效团的设计中。大黄素是一种从大黄中分离出来的天然蒽醌，已知可被细胞色素P450酶代谢，是其中的一种，被用作先导化合物。大黄素对P450s 1A1、1A2、2B1均有抑制作用，IC50值分别为12.25、3.73、14.89 μM。在大黄素分子结构的基础上，进一步在PubChem和ZINC化学数据库中进行相似性检索，鉴定出12个大黄素类似物，用于检测p450的1A1-、1A2-、2B1-和2a6依赖性活性。1-氨基-4-氯-2-甲基-蒽-9,10-二酮（化合物1）对P450 - 1A1的抑制效果最好，IC50值为0.40 μM。1-氨基-4-氯-2-甲基蒽-9,10-二酮（化合物1）和1-氨基-4-羟基蒽-9,10-二酮（化合物2）均抑制P450 - 1A2， IC50值相同，均为0.53 μM。此外，化合物1作为细胞色素P450s 1A1和1A2的机制抑制剂，对p4501a1的KI和Kinactivation值分别为5.38 μM和1.57 min−1，对p4501a2的KI和Kinactivation值为0.50 μM和0.08 min−1。2,6-二叔丁基-5-羟基萘-1,4-二酮（化合物8）直接抑制P450 2B1，具有良好的选择性和抑制效能（IC50 = 5.66 μM）。利用酶的三维结构对所有化合物进行对接研究。这些化合物的结合模式揭示了其效力和选择性的结构特征。化合物1在结构上与化合物2相似，在1位存在一个氨基，对P450s 1A1和1A2的抑制机制不同。化合物1的抑制机制可能归因于2位甲基的存在，靠近氨基。化合物2，在其他方面类似，缺乏甲基部分，没有表现出基于机制的抑制作用。
In silico docking studies and quantitative structure–activity relationship analysis of a number of in-house cytochrome P450 inhibitors have revealed important structural characteristics that are required for a molecule to function as a good inhibitor of P450 enzymes 1A1, 1A2, 2B1, and/or 2A6. These insights were incorporated into the design of pharmacophores used for a 2D search of the Chinese medicine database. Emodin, a natural anthraquinone isolated from Rheum emodi and known to be metabolized by cytochrome P450 enzymes, was one of the hits and was used as the lead compound. Emodin was found to inhibit P450s 1A1, 1A2, and 2B1 with IC50 values of 12.25, 3.73, and 14.89 μM, respectively. On the basis of the emodin molecular structure, further similarity searches of the PubChem and ZINC chemical databases were conducted resulting in the identification of 12 emodin analogues for testing against P450s 1A1-, 1A2-, 2B1-, and 2A6-dependent activities. 1-Amino-4-chloro-2-methylan-thracene-9,10-dione (compound 1) showed the best inhibition potency for P450 1A1 with an IC50 value of 0.40 μM. 1-Amino-4-chloro-2-methylanthracene-9,10-dione (compound 1) and 1-amino-4-hydroxyanthracene-9,10-dione (compound 2) both inhibited P450 1A2 with the same IC50 value of 0.53 μM. In addition, compound 1 acted as a mechanism-based inhibitor of cytochrome P450s 1A1 and 1A2 with KI and Kinactivation values of 5.38 μM and 1.57 min−1 for P450 1A1 and 0.50 μM and 0.08 min−1 for P450 1A2. 2,6-Di-tert-butyl-5-hydroxynaphthalene-1,4-dione (compound 8) directly inhibited P450 2B1 with good selectivity and inhibition potency (IC50 = 5.66 μM). Docking studies using the 3D structures of the enzymes were carried out on all of the compounds. The binding modes of these compounds revealed the structural characteristics responsible for their potency and selectivity. Compound 1, which is structurally similar to compound 2 in the presence of an amino group at position 1, showed a difference in the mechanism of inhibition toward P450s 1A1 and 1A2. The mechanism-based inhibition seen for compound 1 may be attributed to the presence of the methyl group at the 2-position, in close proximity to the amino group. Compound 2, which is otherwise similar, lacks that methyl moiety and did not show mechanism-based inhibition.