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Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids

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  • Hong-Jin Tang
  • Li-Jun Ruan
  • Hai-Yan Tian
  • Guang-Ping Liang
  • Wen-Cai Ye
  • Eleri Hughes
  • Mikael Esmann
  • Natalya U. Fedosova
  • Tse-Yu Chung
  • Jason T. C. Tzen
  • Ren-Wang Jiang
  • David Andrew Middleton
Article number29155
<mark>Journal publication date</mark>5/07/2016
<mark>Journal</mark>Scientific Reports
Issue number6
Number of pages10
Publication StatusPublished
<mark>Original language</mark>English


Cardiotonic steroids (CTS) are clinically important drugs for the treatment of heart failure owing to their potent inhibition of cardiac Na+, K+-ATPase (NKA). Bufadienolides constitute one of the two major classes of CTS, but little is known about how they interact with NKA. We report a remarkable stereoselectivity of NKA inhibition by native 3β-hydroxy bufalin over the 3α-isomer, yet replacing the 3β-hydroxy group with larger polar groups in the same configuration enhances inhibitory potency. Binding of the two 13C-labelled glycosyl diastereomers to NKA were studied by solid-state NMR (SSNMR), which revealed interactions of the glucose group of the 3β- derivative with the inhibitory site, but much weaker interactions of the 3α- derivative with the enzyme. Molecular docking simulations suggest that the polar 3β-groups are closer to the hydrophilic amino acid residues in the entrance of the ligand-binding pocket than those with α-configuration. These first insights into the stereoselective inhibition of NKA by bufadienolides highlight the important role of the hydrophilic moieties at C3 for binding, and may explain why only 3β-hydroxylated bufadienolides are present as a toxic chemical defence in toad venom.