Studies of binding modes of (S)-mephenytoin to wild types and mutants of cytochrome P4502C19 and 2C9 using homology modeling and computational docking
Studies of binding modes of (S)-mephenytoin to wild types and mutants of cytochrome P4502C19 and 2C9 using homology modeling and computational docking
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DOI：
10.1007/s11095-004-7680-8
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发表时间：
2004-12-01
影响因子：
3.7
通讯作者：
Hirono, S
中科院分区：
文献类型：
--
作者：
Oda, A;Yamaotsu, N;Hirono, S
目的。本研究用计算方法研究了与(S)-美苯妥因络合的细胞色素P450_2C19的结构特征。除了野生型的具有S-美苯妥因4-羟基酶活性的野生型蛋白(1A和1B)外，还研究了野生型和人工突变体。以兔CYP2C5的晶体结构为参照，通过同源模建，对野生型和突变型蛋白的三维结构进行了估算。采用计算对接的方法研究了(S)-美苯妥因与细胞色素P450-C19的结合方式。结果重现了(S)美苯妥因与野生型细胞色素P450 2C19的特异性结合。我们的发现表明，CYP2C19的Asp293在(S)-美苯妥因的结合中起着重要作用，它被Val113和Ala297包围，并将苯环指向血红素铁。除野生型CYP2C19的计算对接研究外，还解释了野生型和突变型CYP2C19蛋白的实验活性。这些结果证实了预测的CYP2C19-(S)-美苯妥因络合物的三维结构是合理的，并且该策略对于复杂结构的研究是有用的。还可以使用这些方法进行药物发现的虚拟筛选。
Purpose. This study investigated the structural features of CYP2C19 complexed with (S)-mephenytoin, using computational methods. In addition to wild-type CYP2C19 proteins (1A and 1B), which have selective 4-hydroxylase activities of (S)-mephenytoin, CYP2C19 mutants were also studied, together with a wild type and artificial mutants of CYP2C19.Methods. Three-dimensional structures of wild-type and mutant proteins of CYP2C19 and CYP2C9 were estimated from homology modeling using the crystal structure of rabbit CYP2C5 as a reference. The binding mode of (S)-mephenytoin to CYP2C19 was investigated using computational docking.Results. The results reproduced the specific bindings between (S)mephenytoin and the wild types of CYP2C19. Our findings suggest that Asp293 of CYP2C19 plays an important role in the binding of (S)-mephenytoin, which was surrounded by Val113 and Ala297, and points the phenyl ring at the heme iron. In addition the wild types of CYP2C19, the computational docking studies also accounted for the experimental activities of CYP2C19 mutants, and wild-type and mutant CYP2C19 proteins.Conclusions. These results confirm that the predicted three-dimensional structure of the CYP2C19-(S)-mephenytoin complex is reasonable, and that this strategy is useful for investigating complex structures. Virtual screening for drug discovery can also be carried out using these methods.