Molecular recognition of amiloride analogs: a molecular electrostatic potential analysis. 1. Pyrazine ring modifications

Abstract

Ab initio molecular electrostatic potential (MEP) patterns are used to determine the electrostatic requirements for the formation of a stable blocking complex between amiloride analogs and the epithelial sodium channel of Rana ridibunda. MEP maps calculated in the 3-21G(*) and STO-3G basis sets for amiloride and analogs with pyrazine ring modifications are used to interpret differences in the microscopic rate constants for analog-channel binding determined by Li et al. MEP maps of the protonated analogs are correlated to differences in the value of kon, the microscopic association constant. Those analogs with kon values similar to amiloride are found to have a MEP maximum that is localized over the side chain, as well as strong, distinguishing minima in the MEP pattern off the carbonyl oxygen and positions 3, 4, and 5 of the pyrazine ring. MEP maps of a model-encounter complex (protonated analog and formic acid anion) are correlated to differences in koff, the microscopic dissociation constant. The major conclusions of this work are that (1) a stable blocking complex is formed with analogs which have a deep, localized minimum off the 6 position of the pyrazine ring, (2) the stability of the blocking complex is directly related to the depth of that minimum, (3) substitution at position 5 affects not only the depth but also the location and size of the minimum off position 6, and (4) steric factors may influence the optimal binding of the 6-position ligand to the ion channel. The MEP analysis also suggests that the distance between the proton donors of the chelating guanidinium moiety and the deep, localized minimum off position 6 of the pyrazine ring may define an important spatial requirement for all those analogs which form a stable blocking complex with the channel.

Amiloride Conformation: The Effect of Different Crystalline Environments

“…This also suggests that the planar conformation of the protonated amiloride molecule is preferred not only in gas phase and in solution [17,18,20], but also in different crystalline structures [21,22].…”

“…For these molecules this angle is 5.66(9) • and 11.63(7) • , respectively. Also the planar conformation of the protonated form of amiloride is preferred in gas phase and solvent, with the torsion angle O1 C5 C4 N1 value 180 • [17,18,20]. This conformation is stabilized by intramolecular hydrogen bonds between O1 and N6, as well as O1 and N4, which are observed also in the crystalline structures.…”

“…NMR structural investigations of amiloride as well as molecular theoretical calculations of molecular structure have been carried out [17][18][19][20]. The crystal structure of amiloride hydrochloride has been reported only recently [21].…”

Electronic nature of the transition state for nucleoside hydrolase. A blueprint for inhibitor design

“…The single-point ab initio calculations (STO-3G) required to obtain and display electrostatic potentials for a molecule containing 20 non-hydrogen atoms can be performed, and graphically displayed, in approximately 1 h on a medium-sized workstation. Electrostatic potentials have been used to obtain twoor three-dimensional isopotential contours or surfaces, for predicting differences in electrophilicity, nucleophilicity, and binding interactions of biomolecules, and for exploring the role of charged groups on catalysis in proteases (Venanzi et al, 1992;Sjoberg & Politzer, 1990;Lamotte-Brasseur et al, 1990).…”

Density‐functional‐theory study of α‐cyclodextrin inclusion complexes

“…Additionally to the energetic and geometrical analysis, it is known that scalar fields are useful to give insight about where the charge is distributed. In particular, the molecular electrostatic potential (MEP) maps have shown to serve in the analysis for molecular recognition in several fields of research 28–30. For CDs, the MEP has been used to explain their large dipole moment,31, 32 suggesting that CD complexes are mainly stabilized by electrostatic interactions, but this asseveration for gas‐phase complexes is still in discussion 15…”