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Computational Parameterization of Cytochrome P450 inhibitors for
Molecular Dynamics Simulations
André Fonseca, José R. Pinto, Daniel Ribeiro, Igor C. Encarnação, Sérgio F. Sousa, and
Maria João Ramos
REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto,
Rua do Campo Alegre, 687, 4169-007 Porto, Portugal (email: andrefonsecaa@portugalmail.pt).
Cytochromes P450 (CYP) are a diverse group of enzymes found in all domains of life that use
a large number of small and large molecules as substrates in enzymatic reactions. In humans,
CYPs metabolize thousands of endogenous and exogenous compounds. Most CYPs can
metabolize multiple substrates, and many can catalyze multiple reactions, features that account
for their central importance in metabolizing the extremely large number of endogenous and
exogenous molecules. In fact, CYPs are the major enzymes involved in drug metabolism and
bioactivation, accounting for ca. 75% of the total metabolism [1]. The interaction of small
organic molecules and inhibitors with CYPs is therefore of high biological relevance [2,3].
Here we describe the computational parameterization of a total of 185 inhibitors of the
CYP1A1, CYP1A2, CYP2A6, and CYP1B1 families for accurate molecular dynamics
simulations of the interactions between these compounds and CYPs. The parameters obtained
include bond-lengths, angles, and dihedrals and corresponding force constants, and van der
Waals parameters extracted from the General AMBER force field database. In addition, atomic
charges calculated at the HF/6-31G(d) level were also determined with the RESP methodology.
A database containing all these parameters and complemented with the available IC50 values
for corresponding CYPs is currently in preparation, allowing a variety of detailed
computational-based approaches on CYPs-interaction to be performed with increased accuracy
and speed.
Acknowledgments: FCT (BII/REQUIMTE/GQC/2008)
References:
[1] Guengerich, F. P. (2008), Cytochrome p450 and chemical toxicology, Chem. Res. Toxicol., 21, pp.
70-83.
[2] Lori F., da Fonseca, R., Ramos, M. J., Menziani, M. C. (2005), Theoretical quantitative structureactivity
relationships of flavone ligands interacting with cytochrome P450 1A1 and 1A2 isozymes,
Bioorg. Med. Chem., 13, pp. 4366-4374.
[3] Branco, R.J.F., Seifert, A., Budde, A., Urlacher, V. B., Ramos, M. J., Pleiss, J. (2008), Anchoring
effects in a wide binding pocket: The molecular basis of regioselectivity in engineered cytochrome P450
monooxygenase from B. megaterium, Prot. Struct. Funct. Bioinf., 73, pp. 597-607.
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