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Related Experiment Videos

Drug design from the cryptic inhibitor envelope.

Chul-Jin Lee1, Xiaofei Liang2, Qinglin Wu1

  • 1Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.

Nature Communications
|February 26, 2016
PubMed
Summary

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Drug design targeting enzyme LpxC (lipid A biosynthesis) can exploit hidden conformational states. This approach yielded potent picomolar antibiotics against Gram-negative bacteria.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Drug Discovery

Background:

  • Conformational dynamics is crucial for enzyme function but underexplored in drug design.
  • LpxC, an enzyme in Gram-negative bacterial lipid A biosynthesis, is a key antibiotic target.

Purpose of the Study:

  • To investigate if LpxC inhibitors access alternative conformational states.
  • To explore exploiting these "hidden" states for novel antibiotic development.

Main Methods:

  • Nuclear magnetic resonance (NMR) spectroscopy to study inhibitor-target interactions.
  • Analysis of inhibitor binding to LpxC in solution.

Main Results:

  • LpxC inhibitors access minor, dynamically accessible conformational states not seen in crystal structures.

Related Experiment Videos

  • These states form a "cryptic inhibitor envelope" accessible to small molecules.
  • Drug design based on this envelope yielded antibiotics with picomolar inhibition constants.

    • Conclusions:

    • Exploiting inhibitor conformational dynamics can lead to highly potent therapeutics.
    • The cryptic inhibitor envelope approach offers a novel strategy for antibiotic development.
    • This principle may be applicable to optimizing other drug leads.