Quantum chemical analysis of the interactions of transition state analogs with leucine aminopeptidase

The physical nature of the intermolecular interactions between several leucine aminopeptidase inhibitors, transition state analogs differing in functional groups, and various constituents of the enzyme active site was analyzed using the hybrid variation–perturbation decomposition of self-consistent field and second-order Møller–Plesset perturbation theory interaction energies. The electrostatic term constitutes the dominant contribution in the total interaction energy, although the magnitude of the remaining terms—exchange, delocalization, and correlation—seems to be non-negligible. The total MP2 interaction energy and its dominant electrostatic term correlate reasonably well with the experimentally measured activities of the inhibitors. The application of this method for activity prediction of leucine aminopeptidase inhibitors resulted in very good agreement between calculated and measured inhibition constant values. Results confirm that the applied approach can be a valuable tool for structure-based drug design, prediction of binding affinities, determination of protonation state and binding mode in ligand–receptor systems. © 2001 John Wiley & Sons, Inc. Int J Quantum Chem 84: 302–310, 2001