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

The physical nature of the intermolecular interactions between several leuc ine aminopeptidase inhibitors, transition state analogs differing in functi onal groups, and various constituents of the enzyme active site tvas analyz ed using the hybrid variation-perturbation decomposition of self-consistent field and second-order Moller-Plesset perturbation theory interaction ener gies. The electrostatic term constitutes the dominant contribution in the t otal interaction energy, although the magnitude of the remaining terms-exch ange, delocalization, and correlation-seems to be non-negligible. The total MP2 interaction energy and its dominant electrostatic term correlate reaso nably well with the experimentally measured activities of the inhibitors. T he application of this method for activity prediction of leucine aminopepti dase inhibitors resulted in very good agreement between calculated and meas ured inhibition constant values. Results confirm that the applied approach can be a valuable tool for structure-based drug design, prediction of bindi ng affinities, determination of protonation state and binding mode in Ligan d-receptor systems. (C) 2001 John Wiley & Sons, Inc.