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Project
Descriptions: Temperature
Effects on Structure |
Computational Drug Design
Deborah Crittenden, Truclam Nguyen, Fiona Longmore g-aminobutyric acid (GABA),
H2N-CH2-CH2-CH2-COOH, is the major inhibitory amino acid in the brain. Its role is to balance neuronal excitation
and inhibition processes and it has been described as the brain’s natural
calming agent. As a consequence it is
implicated in a number of neurological disorders including epilepsy,
depression, anxiety and Alzheimer’s disease.
GABA activates three major classes of receptor in the brain and we are
interested in predicting how GABA and other model compounds bind to, in
particular, the GABAC receptor.
This involves studying the shapes of the molecules, their charge
distribution, their interaction with water and their interaction with models
of the various binding sites. We have
developed new computational protocols to study the structure and stability of
solvated amino acids and their phosphoric and phosphinic acid analogues. We
have used these calculations, together with experimental results, to
determine the first Quantitative Structure Activity Relationship (QSAR) for
the GABAC receptor. We have also characterized the bioactive
template molecule, TACA, illustrated below. |
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below-plane substitution
here strictly not tolerated below-plane substitution here tolerated, may possess
either agonist or antagonist activity all above-plane substitution tolerated, with agonist
activity |
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The computational protocols we have developed have also been applied to the interaction of GABA (and its analogues) with models of the amino acid residues implicated in the binding sites. Our goals are to identify the GABAC binding site and to generate the first accurate force fields for zwitterionic interactions. This will allow us to understand and develop new, more specific, drugs that act as agonists or antagonists to GABA. Selected Publications: M. J. T.
Jordan, D. L. Crittenden and K. C. Thompson, “Quantum Effects in Loosely
Bound Complexes”, in Advances in Quantum Diffusion Monte Carlo, J. B.
Anderson, S. R. Rothstein Eds.; American Chemical Society:
Washington D. C.; 2007 pp 101-141 D. L. Crittenden, A. Park,
J. Qui, R. B. Silverman, R. K. Duke, G. A. R. Johnston, M. J. T. Jordan and
M. Chebib "Enantiomers of cis-constrained
and flexible 2-substituted GABA analogues exert opposite effects at
recombinant GABAC receptors", Bioorganic and Medicinal Chemistry,
14, 447-455 (2006). D. L. Crittenden, M. Chebib and M. J. T. Jordan "Quantitative Structure-Activity Relationships of GABAC receptor agonists", J. Mol. Struct. (Theochem, 755, 81-89 (2005). pdf (222 kB) D. L.
Crittenden, R. J. Kumar, J. Hanrahan, M. Chebib and M. J. T. Jordan "The
Stabilisation of Zwitterions in Solution: Phosphonic and Phosphinic Acid GABA
analogues", J. Phys. Chem. A, 109, 8398-8409 (2005). D. L.
Crittenden, M. Chebib and M. J. T. Jordan “The Stabilisation of Zwitterions
in Solution: GABA Analogues” J. Phys. Chem. A, 109, 4195-4201 (2005).
D. L.
Crittenden, K. C.Thompson and M. J. T. Jordan “On the Extent of Intramolecular
Hydrogen Bonding in Gas-Phase and Hydrated 1,2-Ethanediol” J. Phys. Chem. A
109, 2971-2977 (2005). D. L. Crittenden, M. Chebib and M. J. T. Jordan “The Stabilisation of Zwitterions in Solution: g-Aminobutyric Acid (GABA)” J. Phys. Chem. A 108, 203-211 (2004). pdf (145 kB) |