Abstract: A scheme to decompose the intermolecular interaction energy of a series of complexes at the semiempirical (SE) level has been developed and validated. The comparative binding energy analysis (COMBINE) (Ortiz, A. R.; Pisabarro, M. T.; Gago, F.; Wade, R. C. J. Med. Chem. 1995, 38, 2681-2691) and the semiempirical quantum mechanical method pairwise energy decomposition (PWD) (Raha, K.; van der Vaart, A. J.; Riley, K. E.; Peters, M. B.; Westerhoff, L. M. Kim, H.; Merz, K. M., Jr. J. Am. Chem. Soc. 2005, 127, 6583-6594) were coupled together to form SE-COMBINE. This approach calculates the residue pairwise electrostatic interaction energies, and QSAR models were built with the energies as descriptors using partial least squares (PLS). The application of SE-COMBINE was used as an investigation of the intermolecular interactions between 88 benzamidine inhibitors and trypsin and to test the ability of this new method to predict binding free energies. The predictive capability of SECOMBINE is shown to be comparable to those of other QSAR methods, and using graphical intermolecular interaction maps (IMMs) enhances the interpretability of receptor-based QSARs.

Authors: Martin B. Peters and Kenneth M. Merz, Jr.

Reference: J. Chem. Theory Comput. 2006, 2, 383-399. (see link for full paper).