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Systematic Development of Molecular Dynamics Parameters for the
Computational Modelling of Farnesyltransferase Inhibitors
José R. Pinto, André Fonseca, 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: jricardo.mpinto@gmail.com).
Farnesyltransferase (FTase) is an important metalloenzyme that catalyses the addition of a
farnesyl group from farnesyl diphosphate (FPP), to a cysteine residue of a protein substrate
containing a typical -CAAX motif at the carboxyl terminus, where C represents a cysteine
residue [1-3]. FTase inhibition evolved as a promising strategic approach to tackle several
diseases including cancer, malaria, Chagas disease, African sleeping sickness, Toxoplasmosis,
Leishmaniasis, progeria and tuberous sclerosis. Presently more than 500 patents describing
FTase inhibitors have been reported [4], a number that makes this enzyme a very important
target in drug design and development efforts. In particular, Molecular dynamics simulations
are a very powerful tool that allows the computational evaluation of the interaction of
inhibitors with the target protein, with atomic level detail and including important features such
as solvation and dynamic effects.
In this communication we report the systematic parameterization of a total of 234 FTase
inhibitors for use with the well-established AMBER biomolecular force field. Parameters
created include the 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 FTase is currently in preparation, allowing a variety of detailed computational-based
approaches on FTase-inhibition to be performed with increased accuracy and speed.
Acknowledgments: FCT (BII/REQUIMTE/GQC/2008)
References:
[1] Park, H. W., Boduluri, S. R., Moomaw, J. F., Casey, P. J., and Beese, L. S.. (1997), Crystal
structure of protein farnesyltransferase at 2.25 angstrom resolution, Science, 275, pp. 1800-1804.
[2]Long, S. B., Casey, P. J., and Beese, L. S. (2002), Reaction path of protein farnesyltransferase at
atomic resolution, Nature, 419, pp. 645-650.
[3] Sousa, S. F., Fernandes, P. A., Ramos, M. J. (2009), The Search for the Mechanism in the Reaction
Catalyzed by Farnesyltransferase, Chem. Eur. J., 15, pp. 4243-4247.
[4] Sousa, S. F., Fernandes, P. A., Ramos, M. J. (2009), Farnesyltransferase Inhibitors: A Detailed
Chemical View on an Elusive Biological Problem, Curr. Med. Chem., 15, pp. 1478-1492.
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