Non-empirical analysis of the nature of the inhibitor–active-site interactions in leucine aminopeptidase

Grembecka, Jolanta; Kędzierski, Paweł; Sokalski, W. Andrzej

doi:10.1016/s0009-2614(99)01012-x

Cited by 15 publications

(35 citation statements)

References 27 publications

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“…The components defined in such a way naturally correspond to the theoretical models of gradually increasing accuracy and numerical effort: (11) Consistent with our previous studies [25,26], the calculations of the electrostatic interaction energy were performed for the interactions of the LAP active site (Fig. 2a) with known leucine aminopeptidase inhibitors: LeuP (phosphonic analog of leucine) [37] and its analogs in which one of the oxygen atoms (O2) was replaced by different substituents (-H, LeuP-H analog; -OCH 3 , LeuP-OCH 3 analog; -CH 3 , LeuP-CH 3 analog; and -CH 2 Cl, LeuP-CH 2 Cl analog) [37,38] as well as for leucinal [39], LeuB (boronic analog of leucine) [40], LeuP-OH (the LeuP analog with the hydroxyl group instead of the amino group) [38], and IAP (isoamylophosphonate) [37] (Fig.…”

Section: Methodssupporting

confidence: 85%

“…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.…”

Section: Introductionmentioning

confidence: 89%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Electrostatic models of inhibitory activity

Grembecka¹,

Kędzierski²,

Sokalski³

et al. 2001

Int J of Quantum Chemistry

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Various models of electrostatic interactions have been applied and tested for several leucine aminopeptidase (LAP) inhibitors interacting with the enzyme active site. Our results indicate that atomic multipoles up to quadrupole moment as well as potential derived Merz-Kollman and RESP charges reproduce reasonably the ab initio electrostatic interaction energies and the expectation values of the molecular electrostatic potential. These electrostatic models together with CHELP atomic point charges, yield the satisfactory correlation of the electrostatic interaction energy with the experimental activities of the inhibitors, in contrast to the results obtained from atomic monopoles (Mulliken charges) and atomic dipoles. Reasonable correlation has been also obtained for the simple electrostatic "key-lock" model proposed by Náray-Szabó, in which the LAP active site is represented by set of point charges ("lock") interacting with the molecular electrostatic potential of each inhibitor ("key").

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Section: Methodssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Electrostatic models of inhibitory activity

Grembecka¹,

Kędzierski²,

Sokalski³

et al. 2001

Int J of Quantum Chemistry

Self Cite

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show abstract

“…In this model, amino acid residues were truncated to small groups reproducing interactions determined in the active site of enzyme (Fig. (6)) [46]. A set of phosphonic inhibitors of leucine aminopeptidase (22,24,25,26,28) was evaluated in that manner.…”

Section: Methodsmentioning

confidence: 99%

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

Berlicki¹,

Kafarski

2005

COC

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A structure-based approach to design potent and selective inhibitors is an important component of the modern drug development process. As the altered activity of certain enzymes is associated with variety of pathologies, the design and synthesis of inhibitors for enzymes playing the key role in pathogenesis may result in potential therapeutic agents. Nowadays, the development of new inhibitors is often based on computer assisted design process. Although threedimensional structure of the enzyme and mechanism of enzymatic reaction are most important for accurate design, the mode of action of already known lead compounds as well as their characteristic structural features also have to be considered.This review summarises the current progress in computer-aided design of phosphonic and phosphinic acids and their short peptides as inhibitors of chosen enzymes of medical and agrochemical importance. Despite the mechanism of inhibitory activity two approaches for their design are presented. First one relies on the use of the crystal structure of enzymes as well as enzymes complexed with some ligands for structure-based search for novel inhibitory structures. Second enables prediction of activity of new enzyme groups of inhibitors based on the building-up relation of observed activity to specific structural features of sets of compounds of known biological activity.

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

Grembecka

Sokalski

Kafarski

2001

Int J of Quantum Chemistry

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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.

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Non-empirical analysis of the nature of the inhibitor–active-site interactions in leucine aminopeptidase

Cited by 15 publications

References 27 publications

Electrostatic models of inhibitory activity

Electrostatic models of inhibitory activity

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

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

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