Malleability and versatility of cytochrome P450 active sites studied by molecular simulations

Current Drug Metabolism

Volumn 13, Issue 2, 2012, Pages 190-196

  Oostenbrink, Chris ^a,b   De Ruiter, Anita ^b   Hritz, Jozef ^c   Vermeulen, Nico ^a  

^a LEIDEN UNIVERSITY   (Netherlands)

^b UNIVERSITY OF NATURAL RESOURCES AND LIFE SCIENCES   (Austria)

^c UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

Molecular docking; Molecular dynamics simulations; Protein flexibility; Replica exchange; Site of metabolism prediction

Indexed keywords

CHLORPROMAZINE; CYTOCHROME P450; CYTOCHROME P450 1A2; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; PROPRANOLOL; TAMOXIFEN;

ARTICLE; BINDING AFFINITY; BINDING SITE; CRYSTAL STRUCTURE; ENZYME ACTIVE SITE; ENZYME CONFORMATION; LIGAND BINDING; MOLECULAR DYNAMICS; PROTEIN STRUCTURE; STATIC ELECTRICITY;

CATALYTIC DOMAIN; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; LIGANDS; MOLECULAR DYNAMICS SIMULATION; SUBSTRATE SPECIFICITY;

EID: 84857515550     PISSN: 13892002     EISSN: 18755453     Source Type: Journal    
DOI: 10.2174/138920012798918453     Document Type: Article

References (46)

1. Ortiz de Montellano, P. R., Cytochrome P450: Structure, mechanism and biochemistry. Kluwer Academic/Plenum Publishers: New York, 2005.
2. Guengerich, F., P,, A malleable catalyst dominates the metabolism of drugs. Proc. Nat. Acad. Sci. USA, 2006, 103, 13565-13566. (Pubitemid 44413947)
3. Mestres, J., Structure conservation in Cytochromes P450. Proteins, 2005, 58, 596-609. (Pubitemid 40176032)
4. Skopalik, J.; Anzenbacher, P.; Otyepka, M., Flexibility of human Cytochromes P450: Molecular dynamics reveals differences between CYPs 3A4, 2C9 and 2A6, which correlate with their substrate preferences. J. Phys. Chem. B., 2008, 112, 8165-8173.
5. Hendrychová, T.; Berka, K.; Navrátilova, V.; Anzenbacher, P.; Otyepka, M., Dynamics and hydration of the active sites of mammalian cytochromes P450 probed by molecular dynamics simulations. Curr. Drug Metab., 2012, 13(2): 177-189.
6. Ekroos, M.; Sjögren, T., Structural basis for ligand promiscuity in cytochrome P450 3A4. Proc. Nat. Acad. Sci. USA, 2006, 103, 13782-13687.
7. van Gunsteren, W. F.; Bakowies, D.; Baron, R.; Chandrasekhar, I.; Christen, M.; Daura, X.; Gee, P.; Geerke, D.; Glättli, A.; Hünenberger, P. H.; Kastenholz, M. A.; Oostenbrink, B. C.; Schenk, M.; Trzesniak, D.; van der Vegt, N. F. A.; Yu, H. B., Biomolecular modeling: Goals, problems, perspectives. Angew. Chem. Intnl. Ed. 2006, 45, 4064-4092. (Pubitemid 44105659)
8. Carlson, H. A., Protein flexibility and drug design: How to hit a moving target. Curr. Opin. Chem. Biol., 2002, 6, (447 -452).
9. Stjernschantz, E.; Vermeulen, N. P. E.; Oostenbrink, C., Computational prediction of drug binding and rationalisation of selectivity towards cytochromes P450. Exp. Opin. Drug Metab. Tox., 2008, 4, 513-527. (Pubitemid 351890736)
10. Rose, P. W.; Beran, B.; Bi, C. X.; Bluhm, W. F.; Dimitropoulus, D.; Goodsell, D. S.; Prlic, A.; Quesada, M.; Quinn, G. B.; Westbrook, J. D.; Young, J.; Yukick, B.; Zardecki, C.; Berman, H. M.; Bourne, P. E., The RCSB protein data bank: Redesighned web site and web services. Nucl. Acids. Res., 2011, 39, D392-D401.
11. Sansen, S.; Yano, J. K.; Reynald, R. L.; Schoch, G. A.; Griffin, K. J.; Stout, C. D.; Johnson, E. F., Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2. J. Biol. Chem., 2007, 282, 14348-14355. (Pubitemid 47100434)
12. Wester, M. R.; Yano, J. K.; Schoch, G. A.; Yang, C.; Griffin, K. J.; Stout, C. D.; Johnson, E. F., The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-Å resolution. J. Biol. Chem., 2004, 279, 35630-35637. (Pubitemid 39100565)
13. Rowland, P.; Blaney, F. E.; Smyth, M. G.; Jones, J. J.; Leydon, V. R.; Oxbrow, A. K.; Lewis, C. J.; Tennant, M. M.; Modi, S.; Eggleston, D. S.; Chenery, R. J.; Bridges, A. M., Crystal structure of human cytochrome P450 2D6. J. Biol. Chem., 2005, 281, 7614-7622.
14. Hritz, J.; de Ruiter, A.; Oostenbrink, C., Impact of plasticity and flexibility on docking results for Cytochrome P450 2D6: A combined approach of molecular dynamics and ligand docking. J. Med. Chem., 2008, 51, 7469-7477.
15. Stjernschantz, E.; Oostenbrink, C., Improved ligand-protein binding affinity predictions using multiple binding modes. Biophys. J., 2010, 98, 2682-2691.
16. Vasanthanathan, P.; Olsen, L.; Jorgensen, F. S.; Vermeulen, N. P. E.; Oostenbrink, C., Computational prediction of binding affinity for CYP1A2-ligand complexes using empirical free energy calculations. Drug Metab. Disp., 2010, 38, 1347-1354.
17. Jones, G.; Willet, P.; Glen, R. C.; Leach, A. R.; Taylor, R., Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol., 1997, 267, 727-748. (Pubitemid 27170693)
18. Eldritch, M. D.; Murray, C. W.; Auton, T. R.; Paolini, G. V.; Mee, R. P., Empricial scoring functions 0.1. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J. Comp.-Aid. Mol. Des., 1997, 11, 425-445. (Pubitemid 127505895)
19. Kirton, S. B.; Murray, C. W.; Verdonk, M. L.; Taylor, R., Prediction of binding modes for ligands in the Cytochromes P450 and other heme-containing proteins. Proteins, 2005, 58, 836-844. (Pubitemid 40271248)
20. Verdonk, M. L.; Chessari, G.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Nissink, J. W. M.; Taylor, R. D.; Taylor, R., Modeling water molecules in protein-ligand docking using GOLD. J. Med. Chem., 2005, 48, (20), 6504-6415.
21. van Gunsteren, W. F.; Billeter, S. R.; Eising, A. A.; Hünenberger, P. H.; Krüger, P.; Mark, A. E.; Scott, W. R. P.; Tironi, I. G., Biomolecular simulation: The GROMOS96 manual and user guide. Vdf Hochschulverlag AG an der ETH Zürich: Zürich, 1996.
22. Christen, M.; Hünenberger, P. H.; Bakowies, D.; Baron, R.; Bürgi, R.; Geerke, D.; Heinz, T. N.; Kastenholz, M. A.; Kräutler, V.; Oostenbrink, C.; Peter, C.; Trzesniak, D.; van Gunsteren, W. F., The GROMOS software for biomolecular simulation: GROMOS05. J. Comput. Chem., 2005, 26, 1719-1751. (Pubitemid 43076183)
23. Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; Hermans, J., Interaction models for water in relation to protein hydration. In Intermolecular Forces, Pullman, B., Ed. Reidel: Dordrecht, The Netherlands, 1981; pp 331-342.
24. Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; Di-Nola, A.; Haak, J. R., Molecular-dynamics with coupling to an external bath. J. Chem. Phys., 1984, 81, (8), 3684-3690.
25. Ryckaert, J.-P.; Ciccotti, G.; Berendsen, H. J. C., Numerical integration of cartesian equations of motion of a system with constraints: Molecular dynamics of n-Alkanes. J. Comput. Phys., 1977, 23, (3), 327-341.
26. Tironi, I. G.; Sperb, R.; Smith, P. E.; van Gunsteren, W. F., A generalized reaction field method for molecular-dynamics simulations. J. Chem. Phys., 1995, 102, (13), 5451-5459.
27. Heinz, T. N.; van Gunsteren, W. F.; Hünenberger, P. H., Comparison of four methods to compute the dielectric permittivity of liquids from molecular dynamics simulations. J. Chem. Phys., 2001, 115, (3), 1125-1136. (Pubitemid 32699300)
28. Ludemann, S. K.; Lounnas, V.; Wade, R. C., How do substrates enter and products leave the buried active site of cytochrome P450cam? 1. Random expulsion molecular dynamics investigation of ligand access channels and mechanisms. J. Mol. Biol., 2000, 303, 797-811.
29. Ludemann, S. K.; Lounnas, V.; Wade, R. C., How do substrates enter and products exit the buried active site of cytochrome P450cam? 2. Steered molecular dynamics and adiabatic mapping of substrate pathways. J. Mol. Biol., 2000, 303, 813-830.
30. Sugita, Y.; Kitao, A.; Okamoto, Y., Multidimensional replicaexchange method for free-energy calculations. J. Chem. Phys., 2000, 113, (15), 6042-6051.
31. Cojocaru, V.; Winn, P. J.; Wade, R. C., The ins and outs of cytochrome P450s. Biochim. Biophys. Acta, 2007, 1170, 390-401. (Pubitemid 46136742)
32. Souaille, M.; Roux, B., Extension to the weighted histogram analysis method: Combining umbrella sampling ith free energy calculations. Comput. Phys. Comm., 2001, 135, 40-57. (Pubitemid 32265281)
33. Doudou, S.; N.A., B.; Henchman, R. H., Standard free energy of binding from a one-dimensional potential of mean force. J. Chem. Theor. Comp., 2009, 5, 909-918.
34. Cruciani, G.; Carosati, E.; De Boeck, B.; Ethirajulu, K.; Mackie, C.; Howe, T.; Vianello, R., MetaSite: Understanding metabolism in human cytochromes from the perspective of the chemist. J. Med. Chem., 2005, 48, 6970-6979. (Pubitemid 41533118)
35. De Graaf, C.; Vermeulen, N. P. E.; Feenstra, K. A., Cytochrome P450 in silico: An integrative modeling approach. J. Med. Chem., 2005, 48, (8), 2725-2755. (Pubitemid 40548088)
36. Afzelius, L.; Hasselgren Arnby, C.; Broo, A.; Carlsson, L.; Isaksson, C.; Jurva, U.; Kjellander, B.; Kolmodin, K.; Nilsson, K.; Reaubacher, F.; Weidolf, L., State-of-the-Art tools for compuational site of metabolism predictions: Comparative analysis, mechanistical insights, and future applications. Drug Metab. Rev., 2007, 39, 61-86.
37. De Graaf, C.; Pospisil, P.; Pos, W.; Folkers, G.; Vermeulen, N. P. E., Binding mode prediction of cytochrome P450 and thymidine kinase protein-ligand complexes by consideration of water and rescoring in automated docking. J. Med. Chem., 2005, 48, 2308-2318. (Pubitemid 40516425)
38. De Graaf, C.; Oostenbrink, C.; Keizers, P. H. J.; Van der Wijst, T.; Jongejan, A.; Vermeulen, N. P. E., Catalytic site prediction and virtual screening accuracy of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking. J. Med. Chem., 2006, 49, 2417-2430.
39. Vasanthanathan, P.; Hritz, J.; Taboureau, O.; Olsen, L.; Jorgensen, F. S.; Vermeulen, N. P. E.; Oostenbrink, C., Virtual screening and prediction of site of metabolism for cytochrome P450 1A2 ligands. J. Chem. Inf. Model., 2009, 49, 43-52.
40. De Graaf, C.; Oostenbrink, C.; Keizers, P. H. J.; van Vugt-Lussenburg, B. M. A.; van Waterschoot, R.; Tschirret-Guth, R.; Commandeur, J. N. M.; Vermeulen, N. P. E., Molecular modelingguided site-directed mutagenesis of cytochrome P450 2D6. Curr. Drug Metab., 2007, 8, 59-77. (Pubitemid 46043892)
41. Santos, R.; Hritz, J.; Oostenbrink, C., The role of water in molecular docking simulations of Cytochrome P450 2D6. J. Chem. Inf. Model. 2010, 10, 55-66.
42. Teixeira, V. H.; Ribeiro, V.; Martel, P. J., Analysis of binding modes of ligands to multiple conformations of CYP3A4. Biochim. Biophys. Acta, 2010, 1804, 2036-2045.
43. Åqvist, J.; Medina, C.; Samuelsson, J. E., New method for predicting binding affinity in computer-Aided drug design. Protein Eng., 1994, 7, (3), 385-391. (Pubitemid 24063137)
44. Keizers, P. H. J.; De Graaf, C.; de Kanter, F. J. J.; Oostenbrink, C.; Feenstra, K. A.; Commandeur, J. N. M.; Vermeulen, N. P. E., Metabolic regio-And stereoselectivity of cytochrome P450 2D6 towards 3,4-methylenedioxy-N- Alkylamphetamines: In silico predictions and experimental validation. J. Med. Chem., 2005, 48, 6117-6127. (Pubitemid 41324619)
45. De Graaf, C.; Oostenbrink, C.; Keizers, P. H. J.; van Vugt-Lussenburg, B. M. A.; Commandeur, J. N. M.; Vermeulen, N. P. E., Free energies of binding of R-And S-propranolol to wildtype and F483A mutant Cytochrome P450 2D6 from molecular dynamics simulations. Eur. Biophys. J., 2007, 36, 589-599. (Pubitemid 47022944)
46. Venhorst, J.; Onderwater, R. C. A.; Meerman, J. H. N.; Commandeur, J. N. M.; Vermeulen, N. P. E., Influence of N-substitution of 7-methoxy-4- (aminomethyl)-coumarin on Cytochrome P450 metabolism and selectivity. Drug Metab. Disp., 2000, 28, 1524-1532.