NDLI: Studies of Binding Modes of (S)-Mephenytoin to Wild Types and Mutants of Cytochrome P450 2C19 and 2C9 Using Homology Modeling and Computational Docking

Content Provider	Springer Nature Link
Author	Oda, Akifumi Yamaotsu, riyuki Hiro, Shuichi
Copyright Year	2004
Abstract	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.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.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.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.
Starting Page	2270
Ending Page	2278
Page Count	9
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	21
Issue Number	12
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2004-12-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	binding mode computational docking cytochrome P450 2C19 homology modeling Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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