New Delhi metallo-β-lactamase-1
(NDM-1) has recently emerged
as a global threat because of its ability to confer resistance to
all common β-lactam antibiotics. Understanding the molecular
basis of β-lactam hydrolysis by NDM is crucial for designing
NDM inhibitors or β-lactams resistant to their hydrolysis. In
this study, for the first time, NMR was used to study the influence
of Zn(II) ions on the dynamic behavior of NDM-1. Our results highlighted
that the binding of Zn(II) in the NDM-1 active site induced several
structural and dynamic changes on active site loop 2 (ASL2) and L9
loops and on helix α2. We subsequently studied the interaction
of several flavonols: morin, quercetin, and myricetin were identified
as natural and specific inhibitors of NDM-1. Quercetin conjugates
were also synthesized in an attempt to increase the solubility and
bioavailability. Our NMR investigations on NDM-1/flavonol interactions
highlighted that both Zn(II) ions and the residues of the NDM-1 ASL1,
ASL2, and ASL4 loops are involved in the binding of flavonols. This
is the first NMR interaction study of NDM-1/inhibitors, and the models
generated using HADDOCK will be useful for the rational design of
more active inhibitors, directed against NDM-1.
A chiral molecular tweezer obtained from (+)‐usnic acid placed in solution in the presence of various aromatic compounds afforded complexes with low association constants. Thus, the X‐ray structure of assembly 3i is presented, where the guest is sandwiched between the two pincers of the tweezer. The association constants for various guests were determined through different methods. Finally, other tweezers with electron‐rich aromatic aldehydes and ketones were prepared from (1R,2R)‐1,2‐diaminocyclohexane. The most interesting complexes were also confirmed through structural analysis, and the best results were obtained with 10‐hydroxyphenanthrene‐9‐carbaldehyde (5i) as the aromatic moiety.
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