Heuristic lipophilicity potential for computer-aided rational drug design.

In this contribution we suggest a heuristic molecular lipophilicity potential (HMLP), which is a structure-based technique requiring no empirical indices of atomic lipophilicity. The input data used in this approach are molecular geometries and molecular surfaces. The HMLP is a modified electrostatic potential, combined with the averaged influences from the molecular environment. Quantum mechanics is used to calculate the electron density function rho(r) and the electrostatic potential V(r), and from this information a lipophilicity potential L(r) is generated. The HMLP is a unified lipophilicity and hydrophilicity potential. The interactions of dipole and multipole moments, hydrogen bonds, and charged atoms in a molecule are included in the hydrophilic interactions in this model. The HMLP is used to study hydrogen bonds and water-octanol partition coefficients in several examples. The calculated results show that the HMLP gives qualitatively and quantitatively correct, as well as chemically reasonable, results in cases where comparisons are available. These comparisons indicate that the HMLP has advantages over the empirical lipophilicity potential in many aspects. The HMLP is a three-dimensional and easily visualizable representation of molecular lipophilicity, suggested as a potential tool in computer-aided three-dimensional drug design.