|
Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. August 2004, Volume 3, Number 8, 443-463 |
A Graphical Similarity Function to Help Ligand Docking to
Proteins Based on the Molecular Lipophilicity Potential.
The Case of the D2 Dopamine Receptor
Pierre-Alain Carrupt, Isabelle Raynaud, David McLoughlin, Géraldine Bouchard, Patrick Gaillard, Frédéric Billois, Patrizia Crivori, Philip G. Strange, and Bernard Testa
Internet Electron. J. Mol. Des. 2004, 3, 443-463
|
Abstract:
Several recognition forces involved in ligand-receptor binding
are also expressed in lipophilicity. Based on the molecular
lipophilicity potential (MLP), a graphical tool for visual help in
the docking procedure was developed and tested with the
docking of dopamine agonists in a model of trans-membrane
domain of the D2 dopamine receptor built by homology. The
MLP similarity function used in this study was built using two
Molecular Lipophilicity Potential calculated on the ligand
molecular surface, namely the intrinsic MLP (i.e. the MLP of
the ligand) and the perceived MLP (i.e. the MLP generated by
the binding site, and hence perceived by the ligand). The MLP
similarity function tool allows to rank the low-energy
conformers of a ligand-protein complex, thus affording a
criterion to select high-probability binding modes.
Interestingly the procedure was also able to correctly predict
enantioselectivity. The MLP similarity score presented here is
a graphical tool able to analyze recognition forces between a
ligand and a binding site. This method also allows an
explanation of the difference in affinity of D2 receptor between
two enantiomers of a ligand and between two structurally
related compounds.
|