Ab initio molecular modeling in the study of drug metabolism

European Journal of Drug Metabolism and Pharmacokinetics

Volumn 22, Issue 4, 1997, Pages 283-289

  Segall, M D ^a   Payne, M C ^a   Ellis, S W ^b   Tucker, G T ^b   Boyes, R N ^c  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b UNIVERSITY OF SHEFFIELD   (United Kingdom)

^c ML Laboratories Plc ^*  (United Kingdom)

Author keywords

ab initio; Cytochrome P450; Drug metabolism; Molecular modeling

Indexed keywords

CYSTEINE; CYTOCHROME P450; HEME; IRON;

ACCURACY; ATOM; CHEMICAL BINDING; CONFERENCE PAPER; DRUG ACTIVATION; DRUG METABOLISM; ENZYME MECHANISM; MOLECULAR MODEL; QUANTUM MECHANICS;

EID: 0031405918     PISSN: 03787966     EISSN: None     Source Type: Journal    
DOI: 10.1007/BF03190958     Document Type: Conference Paper

References (23)

1. Waszkowycz B., Clark D.E., Frenkel D. et al. (1994) : Pro-ligand: an approach to de novo molecular design. 2. Design of novel molecules from molecular filed analysis (MFA) models and pharmacophores. J. Med. Chem., 37, 3994-4002.
2. Segall M.D., Payne M.C., Ellis S.W., Tucker G.T., Boyes R. (1997) : An ab intitio approach to the understanding of cytochrome P450 - ligand interactions. Xenobiotica, In press.
3. Segall M.D., Payne M.C., Ellis S.W., Tucker G.T., Boyes R.N. (1997) : First principles calculation of the activity of cytochrome P450. Phys. Rev. E Submitted.
4. Segall M.D., Payne M.C., Ellis S.W., Tucker G.T., Boyes R.N. (1998) : Evidence for stabilisation of low-spin state of cytochrome P450 due to shortening of the proximal haem bond. J. Med. Chem. Submitted
5. Levis D.F.V. (1996) : Cytochromes P450: Structure, Function and Mechanism. London: Taylor and Francis.
6. Poulos T.L., Finzel B.C., Howard A.J. (1986) : Crystal structure of substrate-free Pseudomonas pudita cytochrome P450. Biochemistry, 25, 5314-5322.
7. cam. Biochemistry, 26, 8165.
8. cam and other bacterial P-450 enzymes. In: de Montellano P.R.O. (ed.) Cytochrome P-450. New York: Plenum, 429-503.
9. Fisher M., Sligar S. (1985) : Control of heme protein redox potential and reduction rate: linear free energy relation between potential and ferric spin state equilibrium. J. Am. Chem. Soc., 107, 5018-5019.
10. cam complexed with camphane, thiocamphor and adamantane: factors controlling P450 substrate hydroxylation. Biochemistry, 30, 2674-2684.
11. Poulos T., Raag R. (1992) : Cytochrome P450cam: crystallography, oxygen activation, and electron transfer. FASEB J, 6, 676-679.
12. Chang Y.T., Stiffelman O.B., Loew G.H. (1996) : Computer modeling of 3D structures of cytochrome P450s. Biochimie, 78, 771-779.
13. Harris D., Loew G. (1995) : Prediction of regiospecific hydroxylation of camphor analogs by cytochrome P450(cam). J. Am. Chem. Soc., 117, 2738-2746.
14. Jones J.P. (1996) : Predicting rates of cytochrome-P450-mediated bioactivation. In: DeVito S.C., Garrett R.L. (eds) Designing Safer Chemicals: Green Chemistry for Pollution Prevention. Washington: American Chemical Society, 116-137.
15. Ghosh A., Almlof J., Que Jr L. (1994) : Density functional theoretical study of oxo(porphyrinato)iron(IV) complexes, models of peroxidase compounds i and ii. J. Phys. Chem., 98, 5576-5579.
16. Honenberg P., Kohn W. (1964) : Inhomogeneous electron gas. Phys. Rev. 136, 864B-871B.
17. Kohn W., Sham L.J. (1965) : Self-consistent equations including exchange and correlation effects. Phys. Rev., 140, 1133A-1138A.
18. Lin J.S., Qteish A., Payne M.C., Heine V. (1993) : Optimised and transferable non-local separable pseudopotentials. Phys. Rev., 47, 4174B-4180B.
19. Mulliken R.S. (1955) : Electronic population analysis on LCAO-MO molecular wave functions I. J. Chem. Phys., 23, 1833-1840.
20. Segall M.D., Pickard C.J., Shah R., Payne M.C. (1996) : Population analysis in plane wave electronic structure calculations. Mol. Phys., 89, 571-577.
21. cam. Biochemistry, 28, 917-922.
22. Modi S., Paine M.J., Sutcliffe M.J. et al. (1996) : A model for human cytochrome P450 2D6 based on homology modeling and NMR studies of substrate binding. Biochemistry, 35, 4540-4550.
23. Mackman R., Tschirretguth R.A., Smith G. et al. (1996) : Active-site topologies of human CYP2D6 and its aspartate-301-glutamate, asparagine, and glycine mutants. Arch. Biochem. Biophys., 331, 134-140.