Drug design from the cryptic inhibitor envelope

Chul-Jin Lee, Xiaofei Liang, Qinglin Wu, Javaria Najeeb, Jinshi Zhao, Ramesh Gopalaswamy, Marie Titecat, Florent Sebbane, Nadine Lemaitre, Eric J. Toone and Pei Zhou ()
Additional contact information
Chul-Jin Lee: Duke University Medical Center
Xiaofei Liang: Duke University
Qinglin Wu: Duke University Medical Center
Javaria Najeeb: Duke University Medical Center
Jinshi Zhao: Duke University Medical Center
Ramesh Gopalaswamy: Duke University
Marie Titecat: Inserm, Univ. Lille, CHU Lille, Institut Pasteur de Lille, CNRS, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille
Florent Sebbane: Inserm, Univ. Lille, CHU Lille, Institut Pasteur de Lille, CNRS, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille
Nadine Lemaitre: Inserm, Univ. Lille, CHU Lille, Institut Pasteur de Lille, CNRS, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille
Eric J. Toone: Duke University Medical Center
Pei Zhou: Duke University Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-7

Abstract: 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.

Date: 2016
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms10638 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10638

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms10638

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().