The thermodynamic essence of the reversible inactivation of Na+/K+-transporting ATPase by various digitalis derivatives is relaxation of enzyme conformational energy

Beer, Jacques O. De; Kunze, R.; Herrmann, Irmgard; Portius, H. J.; Mirsalichova, Nailja M.; Abubakirov, N. K.; Repke, K.

doi:10.1016/0005-2736(88)90256-8

Cited by 18 publications

(5 citation statements)

References 29 publications

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“…In this work, we have used CoMFA to generate, for the first time, a 3D-QSAR model and contour maps for the inhibition of Na + ,K + -ATPase by cardiotonic and hormonal steroids. Although a number of investigations of digitalis structure-activity relationships for the inhibition of ATPase activity (26,36,(52)(53)(54) have been performed, none of these studies employed a method of data analysis that was capable of correlating the results to specific chemical properties of the ligands or visualizing the structural features that are important for the receptor-ligand interactions. In addition, we generated a 3D-QSAR model and contour maps for the binding of ligands to 26-10.…”

Section: Resultsmentioning

confidence: 99%

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Three-Dimensional Quantitative Structure−Activity Relationship Study of the Inhibition of Na⁺,K⁺-ATPase by Cardiotonic Steroids Using Comparative Molecular Field Analysis

et al. 2001

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Na(+),K(+)-ATPase is a transmembrane protein that transports sodium and potassium ions across cell membranes during an activity cycle that uses the energy released by ATP hydrolysis. Cardiotonic steroids (digitalis) inhibit this activity and consequently produce a positive inotropic response in the heart. To identify the structural features of the steroids that are important for this inhibition, we have tested the inhibitory properties of 47 cardiotonic and hormonal steroids and developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model for the inhibition of Na(+),K(+)-ATPase using comparative molecular field analysis (CoMFA). We also developed a 3D-QSAR model for the binding of digoxin to the murine anti-digoxin monoclonal antibody (mAb) 26-10 because we have previously shown that the environment of the binding sites of 26-10 and the enzyme are similar (Kasturi et al. (1998) Biochemistry 37, 6658-6666). These statistically predictive 3D-QSAR models indicate that both binding sites are about 20 A long and have a close fit or complementarity about the beta side of the lactone ring of digitalis. Furthermore, steric bulk about the lactone ring and the alpha sugar may be critical for drug binding. However, the binding site of Na(+),K(+)-ATPase differs from that of mAb in that it has a greater number of electrostatic interactions along the alpha-sugar, steroid, and lactone moieties. In addition, the availability of the structure of the 26-10 Fab-digoxin complex (Jeffrey et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10310-10314) enabled us to compare the CoMFA-derived contour maps with the known locations for amino acid residues comprising the mAb ligand binding site.

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Section: Resultsmentioning

confidence: 99%

“…Structure−activity studies of the inhibition of Na + ,K + -ATPase by cardiotonic compounds have generated large databases of −Δ G ° values ( − ). In this paper, we present a new approach to investigate the interaction of these compounds with their receptor.…”

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Three-Dimensional Quantitative Structure−Activity Relationship Study of the Inhibition of Na⁺,K⁺-ATPase by Cardiotonic Steroids Using Comparative Molecular Field Analysis

et al. 2001

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“…Structurally, cardiac glycosides are composed of three major components, a steroid ring system, a five- or six-membered lactone moiety, and at least one carbohydrate residue. A substantial number of studies with natural and synthetic cardiac glycosides have generated a body of evidence characterizing the effects of structural modifications on the inhibitory activities of these compounds on various isoforms of Na/K-ATPase ( − ). Most of the inhibitors that were tested in those studies displayed the conserved four-membered steroid ring system of the digoxin skeleton with modifications at the carbohydrate and lactone moieties and at selected positions of the steroid ring system.…”

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Interactions between Cardiac Glycosides and Sodium/Potassium-ATPase: Three-Dimensional Structure−Activity Relationship Models for Ligand Binding to the E₂-P_i Form of the Enzyme versus Activity Inhibition

2004

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Sodium/potassium-ATPase (Na/K-ATPase) is a transmembrane enzyme that utilizes energy gained from ATP hydrolysis to transport sodium and potassium ions across cell membranes in opposite directions against their chemical and electrical gradients. Its transport activity is effectively inhibited by cardiac glycosides, which bind to the extracellular side of the enzyme and are of significant therapeutic value in the treatment of congestive heart failure. To determine the extent to which high-affinity binding of cardiac glycosides correlates with their potency in inhibiting pump activity, we determined experimentally both the binding affinities and inhibitory potencies of a series of 37 cardiac glycosides using radioligand binding and ATPase activity assays. The observed variations in key structural elements of these compounds correlating with binding and inhibition were analyzed by comparative molecular similarity index analysis (CoMSIA), which allowed a molecular level characterization and comparison of drug-Na/K-ATPase interactions that are important for ligand binding and activity inhibition. In agreement with our earlier comparative molecular field analysis studies [Farr, C. D., et al. (2002) Biochemistry 41, 1137-1148], the CoMSIA models predicted favorable inhibitor interactions primarily at the alpha-sugar and lactone ring moieties of the cardiac glycosides. Unfavorable interactions were located about the gamma-sugar group and at several positions about the steroid ring system. Whereas for most compounds a correlation between binding affinity and inhibitory potency was found, some notable exceptions were identified. Substitution of the five-membered lactone of cardenolides with the six-membered lactone of bufadienolides caused binding affinity to decline but inhibitory potency to increase. Furthermore, while the removal of ouabain's rhamnose moiety had little effect on inhibitory potency, it caused a dramatic decline in ligand binding affinity.

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“…AcoA as a cardiac glycoside is expected to inhibit the Na 1 /K 1 -ATPase as well. However, this effect of cardiac glycosides is reversible (Beer et al, 1988). In fact, AcoA does not lead to permanent impairment of the membrane-bound ion pump integrity, but rather protects them against adverse effects of doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

The Cardenolide Glycoside Acovenoside A Affords Protective Activity in Doxorubicin-Induced Cardiotoxicity in Mice

Ezzat

Gaafary

Sayed

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The current study aimed to investigate the protective effect of the cardenolide glycoside acovenoside A (AcoA) against doxorubicininduced cardiotoxicity in mice. AcoA was isolated from the pericarps of Acokanthera oppositifolia to chemical homogeneity and characterized by means of one-and two-dimensional nuclear magnetic resonance spectroscopy. AcoA exhibited relatively low toxicity in mice (LD 50 5 223.3 mg/kg bw). Repeated administration of doxorubicin induced cardiotoxicity manifested by reduced activity of myocardial membrane-bound ion pumps and elevated serum biomarkers of myocardial dysfunction, oxidative stress, and inflammation. Pretreatment of doxorubicin-exposed mice with AcoA (11.16 or 22.33 mg/kg bw, i.p.) for 2 weeks after 2 weeks of combined administration of AcoA and doxorubicin protected the animals dose dependently against doxorubicininduced cardiotoxicity as indicated by normalization of the levels of different myocardial markers of oxidative stress (malondialdehyde, nitric oxide, total antioxidant capacity, and cardiac glutathione), serum myocardial diagnostic marker enzymes (serum cardiac troponin T, creatine kinase isoenzyme MB, aspartate aminotransferase, and lactate dehydrogenase), and inflammatory markers (c-reactive protein, tumor necrosis factor-a, and interleukin-6), as well as myocardial Na 1 /K 1 -ATPase activity. These effects were attributed to the negative impact of AcoA on transcription factors nuclear factor kB and interferon regulatory factor 3/7. Thus acovenoside A might act as a cardioprotective agent to prevent doxorubicin-induced cardiotoxicity.

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The thermodynamic essence of the reversible inactivation of Na+/K+-transporting ATPase by various digitalis derivatives is relaxation of enzyme conformational energy

Cited by 18 publications

References 29 publications

Three-Dimensional Quantitative Structure−Activity Relationship Study of the Inhibition of Na⁺,K⁺-ATPase by Cardiotonic Steroids Using Comparative Molecular Field Analysis

Three-Dimensional Quantitative Structure−Activity Relationship Study of the Inhibition of Na⁺,K⁺-ATPase by Cardiotonic Steroids Using Comparative Molecular Field Analysis

Interactions between Cardiac Glycosides and Sodium/Potassium-ATPase: Three-Dimensional Structure−Activity Relationship Models for Ligand Binding to the E₂-P_i Form of the Enzyme versus Activity Inhibition

The Cardenolide Glycoside Acovenoside A Affords Protective Activity in Doxorubicin-Induced Cardiotoxicity in Mice

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The thermodynamic essence of the reversible inactivation of Na+/K+-transporting ATPase by various digitalis derivatives is relaxation of enzyme conformational energy

Cited by 18 publications

References 29 publications

Three-Dimensional Quantitative Structure−Activity Relationship Study of the Inhibition of Na+,K+-ATPase by Cardiotonic Steroids Using Comparative Molecular Field Analysis

Three-Dimensional Quantitative Structure−Activity Relationship Study of the Inhibition of Na+,K+-ATPase by Cardiotonic Steroids Using Comparative Molecular Field Analysis

Interactions between Cardiac Glycosides and Sodium/Potassium-ATPase: Three-Dimensional Structure−Activity Relationship Models for Ligand Binding to the E2-Pi Form of the Enzyme versus Activity Inhibition

The Cardenolide Glycoside Acovenoside A Affords Protective Activity in Doxorubicin-Induced Cardiotoxicity in Mice

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Three-Dimensional Quantitative Structure−Activity Relationship Study of the Inhibition of Na⁺,K⁺-ATPase by Cardiotonic Steroids Using Comparative Molecular Field Analysis

Three-Dimensional Quantitative Structure−Activity Relationship Study of the Inhibition of Na⁺,K⁺-ATPase by Cardiotonic Steroids Using Comparative Molecular Field Analysis

Interactions between Cardiac Glycosides and Sodium/Potassium-ATPase: Three-Dimensional Structure−Activity Relationship Models for Ligand Binding to the E₂-P_i Form of the Enzyme versus Activity Inhibition