Drug design from the cryptic inhibitor envelope

Nature Communications
Chul-Jin LeePei Zhou

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.

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Citations

Apr 30, 2016·The Journal of Organic Chemistry·Xiaofei LiangPei Zhou
Jul 1, 2016·Annual Review of Microbiology·Jeremy C HendersonM Stephen Trent
Jan 14, 2017·Bioorganic & Medicinal Chemistry Letters·Tetsuya KawaiHaruaki Kurasaki
Jul 17, 2020·Organic & Biomolecular Chemistry·Melanie Rodríguez-AlvaradoStacey E Brenner-Moyer
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Feb 12, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jae ChoPei Zhou
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shuai FanZhaoyong Yang
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Jun 3, 2021·Biomolecules·Florent Sebbane, Nadine Lemaître
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Nov 21, 2018·Journal of Medicinal Chemistry·Gydo C P van ZundertHenry van den Bedem
Sep 30, 2021·Journal of Biomolecular Structure & Dynamics·Rajesh Kumar MeherPradeep K Naik

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Methods Mentioned

BETA
NMR
X-ray

Software Mentioned

HKL2000
PHASER
LBOW
COOT

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