Does electron-correlation has any role in the quantitative structure–activity relationships?

For developing quantitative structure–activity relationships (QSARs), quantum-mechanical molecular descriptors based on the state-of-the-art quantum-mechanical methods such as Hartree–Fock (HF) method and density-functional theory (DFT), are now routinely employed. The validity of these quantum-mechanical methods, however, rests on the accurate estimation of electron-correlation energy. This work analyses the role of electron-correlation, using correlation energy as a molecular descriptor, in the QSARs. In particular, QSAR models, for the mutagenic activity of a set of nitrated polycyclic aromatic hydrocarbons (nitro-PAHs), are examined for the role of electron-correlation through state-of-the-art external validation parameters such as concordance correlation coefficient and recently proposed predictive squared correlation coefficients, namely, QF12, QF22, and QF32 etc. The electron-correlation contribution to the highest occupied and lowest unoccupied molecular orbital (HOMO/LUMO) energies is also analyzed. QSAR models based on the semi-empirical quantum-mechanical methods like PM6 and RM1 are also compared. It is found that the models, developed using electron-correlation contribution of the quantum-mechanical descriptors, are not only robust but also relatively more predictive than those developed with the HF and DFT descriptors. The latter are found to be even less reliable than PM6 and RM1 descriptors based models, which show comparable robustness and predictivity with those developed using electron correlation based descriptors. The external predictivity of model based on semi-empirical descriptors can be improved if electron-correlation contribution of the quantum-mechanical descriptors is explicitly included in the model. This work reports the first-ever use of electron-correlation energy and its contribution to the HOMO/LUMO energies as molecular descriptors.

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► First-ever use of electron-correlation energy as molecular descriptor for QSARs has been reported.
► Electron-correlation descriptor based models are found to be more robust and predictive.
► Hartree–Fock and density functional theory based descriptors are far less reliable.
► HOMO/LUMO energies and electron-correlation have been found to work as best descriptors.
► Advanced semi-empirical methods like RM1 and PM6 based descriptors perform much better.