Theoretical derivation of heuristic molecular lipophilicity potential: a quantum chemical description for molecular...

We present the theoretical derivation of a heuristic molecular lipophilicity potential (HMLP), which gives a structure-based and quantum chemical description of an important aspect of molecular solvation. The quantum mechanical electrostatic potential (ESP) V(r) on a formal molecular surface is calculated, and then the molecular lipophilicity potential L(r) is constructed by comparing the local electron density with the ESP on the surrounding atoms using a screening function. The screening function is derived from statistical mechanical theory treating the polar solvent molecules as dipoles. HMLP is able to describe the main interactions of solute molecules with polar and nonpolar solvent molecules. HMLP is a unified lipophilicity and hydrophilicity potential: its positive values represent lipophilicity, and its negative values represent hydrophilicity. In this paper, several examples show that HMLP gives more reliable descriptions for the molecular solvation than some other methods, such as atomic partial charges and the empirical lipophilicity potential.