2. Academic Validation
  3. Structure of neprilysin in complex with the active metabolite of sacubitril

Structure of neprilysin in complex with the active metabolite of sacubitril

  • Sci Rep. 2016 Jun 15;6:27909. doi: 10.1038/srep27909.
Nikolaus Schiering 1,  Allan D'Arcy 1,  Frederic Villard 1,  Paul Ramage 1,  Claude Logel 1,  Frederic Cumin 1,  Gary M Ksander 2,  Christian Wiesmann 1,  Rajeshri G Karki 2,  Muneto Mogi 2
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.
  • 2 Novartis Institutes for BioMedical Research Inc., 100 Technology Square, Cambridge, Massachusetts, 02139, United States.
PMID: 27302413 DOI: 10.1038/srep27909
Abstract

Sacubitril is an ethyl ester prodrug of LBQ657, the active Neprilysin (NEP) inhibitor, and a component of LCZ696 (sacubitril/valsartan). We report herein the three-dimensional structure of LBQ657 in complex with human NEP at 2 Å resolution. The crystal structure unravels the binding mode of the compound occupying the S1, S1' and S2' sub-pockets of the active site, consistent with a competitive inhibition mode. An induced fit conformational change upon binding of the P1'-biphenyl moiety of the inhibitor suggests an explanation for its selectivity against structurally homologous zinc metallopeptidases.

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