3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design.

Cytochrome P450 2C19 (CYP2C19) is a member of the cytochrome P-450 enzyme superfamily and plays an important role in the metabolism of drugs. In order to gain insights for developing personalized drugs, the 3D (dimensional) structure of CYP2C19 has been developed based on the crystal structure of CYP2C9 (PDB code 1R90), and its structure-activity relationship with the ligands of CEC, Fluvoxamine, Lescol, and Ticlopidine investigated through the structure-activity relationship approach. By means of a series of docking studies, the binding pockets of CYP2C19 for the four compounds are explicitly defined that will be very useful for conducting mutagenesis studies, providing insights into personalization of drug treatments and stimulating novel strategies for finding desired personalized drugs.

[1]  D. Schomburg,et al.  Prediction of protein three-dimensional structures in insertion and deletion regions: a procedure for searching data bases of representative protein fragments using geometric scoring criteria. , 1995, Journal of molecular biology.

[2]  A. Daly,et al.  Pharmacogenetics of the cytochromes P450. , 2004, Current topics in medicinal chemistry.

[3]  Kuo-Chen Chou,et al.  Insights from modelling the 3D structure of the extracellular domain of alpha7 nicotinic acetylcholine receptor. , 2004, Biochemical and biophysical research communications.

[4]  T. A. Jones,et al.  Using known substructures in protein model building and crystallography. , 1986, The EMBO journal.

[5]  S. Narula,et al.  The carboxyl-terminal region of human interferon gamma is important for biological activity: mutagenic and NMR analysis. , 1991, Protein engineering.

[6]  N. Gogtay,et al.  Evaluation of the activity of CYP2C19 in Gujrati and Marwadi subjects living in Mumbai (Bombay) , 2006, BMC clinical pharmacology.

[7]  Kuo-Chen Chou,et al.  Energy of stabilization of the right-handed βαβ crossover in proteins☆ , 1989 .

[8]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[9]  Kuo-Chen Chou,et al.  Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5. , 2004, Biochemical and biophysical research communications.

[10]  K. Chou,et al.  Prediction of the tertiary structure and substrate binding site of caspase‐8 , 1997, FEBS letters.

[11]  K. Chou.  Structural bioinformatics and its impact to biomedical science. , 2004, Current medicinal chemistry.

[12]  K. Chou,et al.  Simulated annealing approach to the study of protein structures. , 1991, Protein engineering.

[13]  M. Tanira,et al.  Frequency of CYP2C9 Genotypes among Omani Patients Receiving Warfarin and Its Correlation with Warfarin Dose , 2006, Public Health Genomics.

[14]  Louise Wickham,et al.  Post-translational Processing of β-Secretase (β-Amyloid-converting Enzyme) and Its Ectodomain Shedding , 2001, The Journal of Biological Chemistry.

[15]  D. Flockhart,et al.  Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism , 2002, Clinical pharmacokinetics.

[16]  E. Korpi,et al.  Impact of ε and θ subunits on pharmacological properties of α3β1 GABAA receptors expressed in Xenopus oocytes , 2006, BMC Pharmacology.

[17]  Kuo-Chen Chou,et al.  Prediction of the Tertiary Structure of the β-Secretase Zymogen☆ , 2002 .

[18]  Kuo-Chen Chou,et al.  Insights from modeling the tertiary structure of human BACE2. , 2004, Journal of proteome research.

[19]  Kuo-Chen Chou,et al.  Identification of the N‐terminal functional domains of Cdk5 by molecular truncation and computer modeling , 2002, Proteins.

[20]  Kuo-Chen Chou,et al.  Insights from modeling the 3D structure of H5N1 influenza virus neuraminidase and its binding interactions with ligands. , 2006, Biochemical and biophysical research communications.

[21]  D. Nebert,et al.  Characterization of the common genetic defect in humans deficient in debrisoquine metabolism , 1988, Nature.

[22]  Louise Wickham,et al.  Post-translational processing of β-secretase (BACE) and its ectodomain shedding: the pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid Aβ production , 2001 .

[23]  K D Watenpaugh,et al.  A model of the complex between cyclin-dependent kinase 5 and the activation domain of neuronal Cdk5 activator. , 1999, Biochemical and biophysical research communications.

[24]  H. Klenk,et al.  Identification and functional characterization of eight CYP3A4 protein variants. , 2001, Pharmacogenetics.

[25]  A. Tomasselli,et al.  The atomic-resolution structure of human caspase-8, a key activator of apoptosis. , 1999, Structure.

[26]  N. Thornberry,et al.  The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis , 1996, Nature Structural Biology.

[27]  Eric F. Johnson,et al.  The Structure of Human Cytochrome P450 2C9 Complexed with Flurbiprofen at 2.0-Å Resolution* , 2004, Journal of Biological Chemistry.

[28]  I. Lauder,et al.  Differences in diazepam pharmacokinetics in Chinese and white Caucasians – Relation to body lipid stores , 2004, European Journal of Clinical Pharmacology.

[29]  L. Tsai,et al.  Structure and Regulation of the CDK5-p25nck5a Complex , 2001 .

[30]  I. Kuntz,et al.  Structure-Based Molecular Design , 1994 .

[31]  I. Kuntz.  Structure-Based Strategies for Drug Design and Discovery , 1992, Science.

[32]  T. L. Blundell,et al.  Knowledge-based prediction of protein structures and the design of novel molecules , 1987, Nature.

[33]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998 .

[34]  K. Chou,et al.  Low-frequency collective motion in biomacromolecules and its biological functions. , 1988, Biophysical chemistry.

[35]  K. Chou,et al.  Progress in computational approach to drug development against SARS. , 2006, Current medicinal chemistry.

[36]  Gerhard Wagner,et al.  Solution Structure of the RAIDD CARD and Model for CARD/CARD Interaction in Caspase-2 and Caspase-9 Recruitment , 1998, Cell.

[37]  V. Garsky,et al.  The Pro Domain of β-Secretase Does Not Confer Strict Zymogen-like Properties but Does Assist Proper Folding of the Protease Domain* , 2001, The Journal of Biological Chemistry.

[38]  K. Chou,et al.  Low-frequency resonance and cooperativity of hemoglobin. , 1989, Trends in biochemical sciences.

[39]  K.-C. Chou,et al.  Anti-SARS drug screening by molecular docking , 2006, Amino Acids.

[40]  Kuo-Chen Chou.  Insights from modeling three-dimensional structures of the human potassium and sodium channels. , 2004, Journal of proteome research.

[41]  Kuo-Chen Chou,et al.  Theoretical studies of Alzheimer's disease drug candidate 3-[(2,4-dimethoxy)benzylidene]-anabaseine (GTS-21) and its derivatives. , 2005, Biochemical and biophysical research communications.

[42]  S. Wodak,et al.  Modelling the polypeptide backbone with 'spare parts' from known protein structures. , 1989, Protein engineering.

[43]  Kuo-Chen Chou,et al.  Modeling the tertiary structure of human cathepsin-E. , 2005, Biochemical and biophysical research communications.

[44]  Kuo-Chen Chou,et al.  Molecular therapeutic target for type-2 diabetes. , 2004, Journal of proteome research.

[45]  David S. Goodsell,et al.  Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4 , 1996, J. Comput. Aided Mol. Des..

[46]  K. Chou,et al.  Prediction of the tertiary structure of a caspase‐9/inhibitor complex , 2000, FEBS letters.

[47]  Fred Glover,et al.  Tabu Search: A Tutorial , 1990 .