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Nat Commun. 2016 Feb 25;7:10638. doi: 10.1038/ncomms10638.

Drug design from the cryptic inhibitor envelope.

Author information

1
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
2
Department of Chemistry, Duke University, Durham, North Carolina 27708, USA.
3
Inserm, Univ. Lille, CHU Lille, Institut Pasteur de Lille, CNRS, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.

Abstract

Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.

PMID:
26912110
PMCID:
PMC4773385
DOI:
10.1038/ncomms10638
[Indexed for MEDLINE]
Free PMC Article

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