Modeling lipophilicity from the distribution of electrostatic potential on a molecular surface.
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, delta(si), and the molecular electrostatic potential (MEP), V(ri), at the center of an area element: B = sigma(i) delta(si) 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 descriptions 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.
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Department of Chemistry and Biochemistry, Laurentian University, Sudbury, ON, Canada.
Arteca
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D000438:Alcohols; D001555:Benzene Derivatives; D002151:Calorimetry; D004563:Electrochemistry; D006838:Hydrocarbons; D008956:Models, Chemical; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013499:Surface Properties
D000438:Alcohols; D001555:Benzene Derivatives; D006838:Hydrocarbons