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

Abstract

ABSTRACT: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.

Electrostatic models of inhibitory activity

“…Moreover, the ab initio electrostatic interaction energy term reasonably correlates with the experimentally measured activities of the inhibitors (the linear regression coefficient, R = 0.92) mimicking the correlation obtained at higher theory levels [linear combination of atomic orbitals, (LCAO), molecular orbital (MO), self-consistent field (SCF), R = 0.94 and MP2, R = 0.95]. These studies indicate that even though involving the remaining terms of the interaction energy (exchange, delocalization, and correlation) may result in a slightly better agreement between theoretical and experimental data, their contribution is less significant and similar for all the inhibitors studied [25,26]. Based on the above findings, we have performed calculations for the electrostatic interaction energy of these inhibitors at the LAP active site, using various approximate models based on different schemes of atomic point charges (Mulliken [11], charges from electrostatic potential; Merz-Kollman [27] and CHELP [8,28]), based on the cumulative atomic multipole moments [29,30], and based on the MEPs.…”

“…Frequently the electrostatic interactions are considered to be the most important for binding differences of these LAP inhibitors. The decomposition of the interaction energy of the LAP active site with these inhibitors reveals the dominant share of the electrostatic term (more than 70%) in the total second-order Möller-Plesset theory (MP2) interaction energy [25,26]. Moreover, the ab initio electrostatic interaction energy term reasonably correlates with the experimentally measured activities of the inhibitors (the linear regression coefficient, R = 0.92) mimicking the correlation obtained at higher theory levels [linear combination of atomic orbitals, (LCAO), molecular orbital (MO), self-consistent field (SCF), R = 0.94 and MP2, R = 0.95].…”

“…These models correspond to different lengths of atomic multipole expansion and completely or par- tially neglect the penetration contribution. Our goal is to compare the results obtained by the application of the approximate methods with recently available nonempirical values of inhibitor-enzyme interaction energy components [25,26], which are unique in the literature. This would allow us to examine which simple theoretical models are sufficient to correctly describe the electrostatic interactions of the inhibitors with the LAP active site residues and to quantitatively reproduce exact ab initio results.…”

Unusual activity pattern of leucine aminopeptidase inhibitors based on phosphorus containing derivatives of methionine and norleucine

“…Met-PH and Nle-PH were practically equipotent with their phosphonic counterparts (compare entries 1 versus 2 and 3 versus 4 in Table 1). Previous reports suggested there should be significantly weaker binding by the zinc ions present in the active site, and thus show a large disparity in their K i values (for example, for leucine analogues this disparity exceeded two orders of magnitude) [49,50]. Thus, the difference in inhibitory activity of compounds 1-4 depended only on the structure of their side chain substituents.…”

Computer-Aided Analysis and Design of Phosphonic and Phosphinic Enzyme Inhibitors as Potential Drugs and Agrochemicals

“…Next, quantum chemical analysis was extended to a bigger group of inhibitors (20)(21)(22)(23)(24)(25)(26)(27)(28) [47][48][49]. Significant correlation between experimental pK i values and MP2 interaction energies was obtained as well.…”