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Structure–Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product
journal contribution
posted on 2017-02-07, 00:00 authored by Hai L. Tran, Katrina W. Lexa, Olivier Julien, Travis S. Young, Christopher T. Walsh, Matthew P. Jacobson, James A. WellsMacrocycles
are appealing drug candidates due to their high affinity,
specificity, and favorable pharmacological properties. In this study,
we explored the effects of chemical modifications to a natural product
macrocycle upon its activity, 3D geometry, and conformational entropy.
We chose thiocillin as a model system, a thiopeptide in the ribosomally
encoded family of natural products that exhibits potent antimicrobial
effects against Gram-positive bacteria. Since thiocillin is derived
from a genetically encoded peptide scaffold, site-directed mutagenesis
allows for rapid generation of analogues. To understand thiocillin’s
structure–activity relationship, we generated a site-saturation
mutagenesis library covering each position along thiocillin’s
macrocyclic ring. We report the identification of eight unique compounds
more potent than wild-type thiocillin, the best having an 8-fold improvement
in potency. Computational modeling of thiocillin’s macrocyclic
structure revealed a striking requirement for a low-entropy macrocycle
for activity. The populated ensembles of the active mutants showed
a rigid structure with few adoptable conformations while inactive
mutants showed a more flexible macrocycle which is unfavorable for
binding. This finding highlights the importance of macrocyclization
in combination with rigidifying post-translational modifications to
achieve high-potency binding.
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Keywords
drug candidatesantimicrobial effectsNatural Product MacrocyclesGram-positive bacterialow-entropy macrocyclehigh-potency bindingproduct macrocycleRing Entropy3 D geometrypeptide scaffoldsite-directed mutagenesismodel systemwild-type thiocillinComputational modelingrigidifying post-translational modificationssite-saturation mutagenesis libraryMolecular Mechanics Revealchemical modifications
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