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"ABSTRACT

Cytochrome P450 isoform 2C9 (CYP2C9) is a main enzyme which metabolizes phenytoin [I]. The inhibition of this enzyme will increase plasma level of phenytoin. Cimetidine is known as drug that inhibits this enzyme, resulting an increased plasma level of phenytoin [2]. Recently, the three dimentional molecular basis of interaction between phenytoin and cimetidine toward CYP2C9 has not been described well yet. The present findings may represent an important advance for understanding interaction CYP2C9 with drugs to predict its toxicity an also metabolism based on structural interaction from docking results. A computational methodology, molecular docking can be used to analyze interaction which exist between ligand and macromolecule. AutoDock is one of the most commonly used methodology, shows the efficiency of scoring function ligand that bound to its active site [3]. So that, it can be used to understand about interaction between phenytoin and cimetidine in CYP2C9. Crystal structure of CYP2C9 complexed with flurbiprofen (PDB ID: 1R90) has resolution 2.00 A. This structure, used in this experiment, has the closed conformational structure and complexed with S-warfarin. Three dimensional structure of phenytoin and cimetidine were minimized, charge were added for docking preparation. Binding of substrate phenytoin in CYP2C9 is stabilized by hidrogen bonds, interaction with cationic residue Argl08, hydrophobic interaction particularly with Phel 14. On the other side, binding of cimetidine inhibitor in CYP2C9 is stabilized by hydrogen bonds with some amino acid residues, including Glu300 which has role as anionic residue, also the exist of hydrophobic interaction. Cimetidine being competitive inhibitor of CYP2C9 at the substrate recognition site of phenytoin. "

"Cytochrome P450 3A4 (CYP3A4) contributes to the metabolism of 50% of drugs used in therapy [l]. Nowadays, the structures of CYP3A4 are available through crystallography technique and these structures show that CYP3A4 has a flexible active site which allows many probabilities of ligand interaction [2]. Nelfinavir, one of the HIV-Protease inhibitors, is a substrate and also an inhibitor of CYP3A4. However, the CYP3A4-mediated metabolism of nelfinavir result in unknown reactive metabolites which then inactivate CYP3A4 [3]. In silica method through molecular docking is used in this research to study the inhibition of CYP3A4 by nelfinavir and to predict the reactive metabolites of nelfinavir that inactivate CYP3A4. The docking result show that nelfinavir fits the CYP3A4 active site with the conformation that coordinates to the forming of M8 metabolite of nelfinavir. The docking result for M8 gives positive binding energy and the docking result for the intermediate metabolite between nelfinavir and M8 indicates that this intermediate metabolite is responsible for the inhibition of CYP3A4 by nelfinavir through mechanism-based inactivation."