Drug design from the cryptic inhibitor envelope.
Drug design from the cryptic inhibitor envelope.
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DOI：
10.1038/ncomms10638
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发表时间：
2016-02-25
影响因子：
16.6
通讯作者：
Zhou P
中科院分区：
文献类型：
--
作者：
Lee CJ;Liang X;Wu Q;Najeeb J;Zhao J;Gopalaswamy R;Titecat M;Sebbane F;Lemaitre N;Toone EJ;Zhou P
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. The conformational dynamics of a compound has a large effect on ligand/receptor binding. Here, the authors employ NMR spectroscopy to study ligand binding to the enzyme LpxC, discovering an inhibitor envelope that was not identifiable by crystallography and subsequently developing a highly potent inhibitor.
