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Homology modeling and molecular dynamics of CYP1A1 and CYP2B1 to explore aryl derivatives metabolism by docking, followed by experimental assays
Author(s) -
MendietaWejebe Jessica Elena,
CorreaBasurto José,
TrujilloFerrara José G.,
RosalesHernández Martha Cecilia
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.967.8
Subject(s) - chemistry , stereochemistry , cytochrome p450 , homology modeling , metabolite , docking (animal) , molecular dynamics , heme , biotransformation , enzyme , hydroxylation , microsome , biochemistry , computational chemistry , medicine , nursing
Since many drugs are metabolized by cytochrome P450 (CYP450), biotransformation studies using these enzymes are valuable in drug development. In this contribution the biotransformation by CYP1A1 and CYP2B1 of two acetylcholinesterase (AChE) inhibitors named 4‐(4′‐hydroxy‐phenylamino)‐4‐oxo propanoic acid ( A ) and 1H‐pyrrolidine‐1‐(4′‐hydroxy‐phenyl)‐2,5‐dione ( B ), was investigated theoretically by molecular modeling (docking and molecular dynamics; MD) and experimentally by using liver microsomes from rats pretreated with β‐naphthoflavone and phenobarbital (CYP1A1/CYP2B1 inducers, respectively). First, the target proteins were built under homology modeling and the resulting three dimensional structures were refined by MD, obtaining fifteen snapshots of each isoform. These conformers were used to dock test compounds A and B . Neither A nor B presented interaction of its amide and imide group, respectively, with the heme on any snapshot of CYP1A1. On the other hand when these compounds were docked on CYP2B1, their hydroxyl group was located near the heme iron on the snapshot at 3.5 ns. Therefore, theoretical results suggests that A and B can not generate toxic metabolites. Supporting these results, HPLC analysis showed only one metabolite from A and B , which was identified by GC‐MS as the hydroxylated product. Consequently, experimental results confirmed that neither test compound is toxic.