Predicting DNA–intercalator binding: the development of an arene–arene stacking parameter from SAPT analysis of benzene‐substituted benzene complexes

A series of substituted naphthalimides were synthesized and intercalated into the DNA sequence d(GCGCGCGC)2, and an experimental ΔTm value was obtained. Two-parameter QSAR analyses were performed to generate a theoretical ΔTm value. Although by no means exhaustive in terms of parameter selection, the correlations did not yield statistics that indicated the models met the threshold for significance at the 95% confidence level. Rather than continue with an exhaustive search of all possible QSAR parameters, a one-parameter QSAR analysis was performed utilizing a novel arene–arene stacking parameter, designated Ππ, developed from Symmetry-Adapted Perturbation Theory (SAPT) energy decomposition studies of calculated benzene-substituted benzene dimer binding energies. The QSAR analysis using the Ππ stacking parameter yielded statistics suggesting the model was significant at the 95% confidence level. The approach of developing a novel QSAR parameter via SAPT calculations, rather than exhaustively searching all traditional QSAR parameters, is presented both as a new approach for QSAR studies and as a unique application of SAPT. Copyright © 2013 John Wiley & Sons, Ltd.