Molecular lipophilicity potential (MLP) in drug design. Complementing theoretical tools with experimental results

The Molecular Lipophilicity Potential (MLP) is a versatile tool in drug design whose present state and potential developments are reviewed here. The MLP offers a three-dimensional representation of lipophilicity as calculated from partition coefficients. The intermolecular recognition forces and intramolecular effects encoded in lipophilicity are presented, followed by the theoretical foundations and validation of the MLP. It is then demonstrated that the MLP allows for the first time to investigate the dependence of lipophilicity on conformation. As a matter of fact, the MLP combined with an exploration of the conformational space of a solute reveals its "chameleonic" behaviour, i.e. its capacity to adapt to the molecular environment. Other applications of the MLP are presented and illustrated, namely its integration into 3D-QSAR (Comparative Molecular Field Analysis, CoMFA) and its interest as a docking tool.