Quantum-chemical study on calcium(II) chelates with ouabagenin

Abstract

Complete conformational analysis of 1 : 1 calcium(II) chelates with ouabagenin was performed ab initio. Analysis of the effect of complex formation on the steric and electronic structures revealed that ouabagenin molecule is capable of coordinating Ca 2+ ion in three different modes. The lack of rhamnose fragment in the ouabagenin molecule, in contrast to ouabain, sharply reduces its physiological activity related to its ability to bind at transducer Na + /K + -ATPase site.Cardiotonic steroids constitute a class of compounds capable of selectively binding to extracellular surface of Na + /K + -ATPase; the latter is an enzyme which utilizes the energy of ATP hydrolysis for active transport of Na + and K + ions through cell membranes [1][2][3][4]. This class of compounds includes both glycosides (such as ouabain and digoxin) and aglycones (ouabagenin, strophadogenin, adonitoxigenin). Clinical applications of cardiotonic steroids is based on their ability to exert a positive inotropic effect on myocard via partial inhibition of Na + /K + -ATPase in myocard cells [4]. The results of recent studies have shown that Na + /K + -ATPase can act as signal transducer which controls nociceptive information transmission in sensor neurons of warm-blooded animals [5], as well as cell growth and proliferation in various tissues [6][7][8][9][10][11][12][13][14].Using the organotypic tissue culture technique, it was shown that ouabain in nanomolar concentration range (which is comparable with the endogenous ouabain level) is capable of modulating transducer function of Na + /K + -ATPase in nervous and cardiac tissues [11][12][13]15]. Ligand-receptor interaction of ouabain molecule with some amino acid sequence of the enzyme is likely to involve formation of the ternary complex ouabain-Ca 2+ -Na + /K + -ATPase [15]. Nonempirical quantum-chemical calculations showed that ouabain molecule is theoretically capable of chelating Ca 2+ ion, and six possible conformations of the complexes thus formed were found [15]. In continuation of our studies on the ability of cardiotonic steroids to modulate transducer activity of Na + /K + -ATPase, we examined the effect of ouabagenin [1β,3β,5β,11α,-14β,19β-hexahydroxycard-20(22)-enolide] on the growth of neurites of sensor ganglia and cardiac tissue explants in 10-12-day chicken embryos using the organotypic tissue culture technique. Ouabagenin at

Modulation of the transducer function of Na+,K+-ATPase: new mechanism of heart remodeling

“…Endogenous ouabain in chelate complex with Ca 2+ ion directly modulates the non-pumping function of Na + ,K + -АТPase (Lopatina et al 2008;Rogachevskii 2008). The remainder rhamnose of ouabain plays a very important role in the realization of its physiological effects (Kipenko et al 2009;Lopatina et al 2008a;Rogachevskii et al 2011). Src-kinase is involved in ouabain-induced modulation of the heart remodeling.…”

Role of the Rhamnosyl Residue of Ouabain in the Activation of the Na,K-ATPase Signaling Function

“…Ab initio RHF/6-31G* conformational analysis of the free ouabain (OUA) and ouabagenin (OBG) molecules, as well as the ouabagenin-Ca 2+ chelate complex (OBG-Ca), was previously performed [11,14,15]. Four stable conformations were detected for both OUA and OBG, differing by the conformation of the ring A (the chair or the twist) and orientation of the lactone ring E, which is allowed to rotate freely with respect to the steroid core.…”

“…Computational approach to the problem quires docking of both molecules with the NKA molecule to provide a detailed insig Once again, our suggestion that EO might be the Ca 2+ chelate complex of ouabain is based on the following results. It has been shown by ab initio calculations that both ouabain and ouabagenin molecules can effectively chelate a Ca 2+ cation, and two possible chelation modes were detected for each molecule [11,14,15]. Patch-clamp experiments carried out on nociceptive neurons of rats confirmed that nanomolar concentrations of ouabain in an excessive presence of Ca 2+ modulate the effective charge (Z eff ) transferred by the Na V 1.8 channel activation gating system, which was attributed to activation of the NKA signaling function [6,11,13].…”

“…Therefore, it is reasonable to expect a substantial difference between EO and OUA in intermolecular interactions formed in their ligand-NKA complexes. At the structural level, it has been shown that Ca 2+ chelation by OUA and ouabagenin (OBG) does not significantly change the ligand geometry [11,14,15]. However, the introduction of a fixed positive charge in the form of a chelated divalent Ca 2+ cation drastically affects the ligand electrostatic properties and would require the cation charge to be compensated by ionic interactions with NKA in the ligand-receptor complex.…”