COSMOsar3D: Molecular Field Analysis Based on Local COSMO σ-Profiles

Abstract

The COSMO surface polarization charge density σ resulting from quantum chemical calculations combined with a virtual conductor embedding has been widely proven to be a very suitable descriptor for the quantification of interactions of molecules in liquids. In a preceding paper, grid-based local histograms of σ have been introduced in the COSMOsim3D method, resulting in a novel 3D-molecular similarity measure and going along with a novel property-based molecular alignment method. In this paper, we introduce under the name COSMOsar3D the usage of the resulting array of local σ-profiles as a novel set of molecular interaction fields for 3D-QSAR, containing all information required for quantifying the virtual ligand-receptor interactions, including desolvation. In contrast to currently used molecular interaction fields, we provide a theoretical rationale that the logarithmic binding constants of ligands should be a linear function of the array of local σ-profiles. This makes them especially suitable for linear regression analysis methods such as PLS. We demonstrate that the usage of local σ-profiles in molecular field analysis inverts the role of ligands and receptor; while conventional 3D-QSAR considers the virtual receptor in potential energy fields provided by the ligands, our COSMOsar3D approach corresponds to the calculation of the free energy of the ligands in a virtual free energy field provided by the receptor. First applications of the COSMOsar3D method are presented, which demonstrate its ability to yield robust and predictive models that seem to be superior to the models generated on the basis of conventionally used molecular fields.