Chemical-physical analysis of a tartrate model compound for TACE inhibition

Phys Chem Chem Phys. 2013 Nov 21;15(43):18881-93. doi: 10.1039/c3cp52955j.

Abstract

We have synthesized and done an extensive chemical-physical analysis of the behavior of a new compound, named MBET306, a synthetic precursor of the recently discovered tartrate-based inhibitors of the protein Tumor Necrosis factor-α Converting Enzyme (TACE). Experimental and theoretical data have shown that in water solution MBET306 is overwhelmingly found as a monoanion at physiological pH, in a conformation that differs substantially from that detected in the known co-crystal structures of MBET306 derivatives bound to TACE. The body of collected experimental and theoretical data indicates that the monoanionic species binds Zn(ii) inducing a strong stabilization of the crystal-like arrangement of the central tartrate zinc-binding group, lending support for a two step TACE docking mechanism via a zinc-bound intermediate. The thorough chemical-physical characterization of the conformational behavior of free and zinc-bound MBET306 in water bulk solution opens new avenues for the rational drug design of tartrate-based highly specific TACE inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Binding Sites
  • Catalytic Domain
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Hydrogen-Ion Concentration
  • Mice
  • Molecular Conformation
  • Molecular Docking Simulation
  • Protein Binding
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism
  • Tartrates / chemistry*
  • Thermodynamics
  • Water / chemistry
  • Zinc / chemistry

Substances

  • 2,3-dihydroxy-4-oxo-N-((R)-1-phenylethyl)-4-(pyrrolidin-1-yl)butanamide
  • Coordination Complexes
  • Enzyme Inhibitors
  • Pyrrolidines
  • Tartrates
  • Water
  • ADAM Proteins
  • ADAM17 Protein
  • Adam17 protein, mouse
  • Zinc
  • tartaric acid