A Graphical Similarity Function to Help Ligand Docking to Proteins Based on the Molecular Lipophilicity Potential. The Case of the D 2 Dopamine Receptor

Motivation. 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. Method. 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). Results. 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. Conclusions. 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.