Modeling lipophilicity from the distribution of electrostatic potential on a molecular surface

Summary

Molecular lipophilicity L is represented as a function of four surface electrostatic potential descriptors: L=f(B_F ⁺,B_F ^-,B_R ⁺,B_R ^-). Each B descriptor is computed from the products of elements of molecular surface area, Δs_i, and the molecular electrostatic potential (MEP), V(r _i), at the center of an area element: B = ∑_i Δ_i V(r_i). Octanol-water partition coefficients (P_ow) are correlated with these four surface-MEP descriptors: log P_ow=c₀+c₁B_F ⁺+c₂B_F ^-+c₃B_R ⁺+c₄B_R ^-. Good correlations are obtained for homologous series of aliphatic alcohols, amines and acids, as well as for a set of aromatic compounds with various functional groups. Within this approach, we find that the molecular fragment contributions of surface-MEP descriptors to log P are approximately additive. We have computed the values for the following fragments:-CH₂-,-CH₃,-COOH,-OH and-NH₂. These contributions can be used to estimate the molecular lipophilicity and partition coefficients of new compounds, without additional quantum-mechanical calculations. The proposed approach provides a reasonably accurate tool that can be useful in quantitative structure-activity relations for computer-aided rational drug design. More importantly, the correlation model is conceptually simpler than previous work in the literature and can be improved systematically.