Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor.

Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor. Research Abstract Details 

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Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor. Abstract Text:

Ajay Mandal,Donald Hilvert,

The highest affinity inhibitor for chorismate mutases, a conformationally constrained oxabicyclic dicarboxylate transition state analogue, was modified as suggested by computational charge optimization methods. As predicted, replacement of the C10 carboxylate in this molecule with a nitro group yields an even more potent inhibitor of a chorismate mutase from Bacillus subtilis (BsCM), but the magnitude of the improvement (roughly 3-fold, corresponding to a DeltaDeltaG of -0.7 kcal/mol) is substantially lower than the gain of 2-3 kcal/mol binding free energy anticipated for the reduced desolvation penalty upon binding. Experiments with a truncated version of the enzyme show that the flexible C terminus, which was only partially resolved in the crystal structure and hence omitted from the calculations, provides favorable interactions with the C10 group that partially compensate for its desolvation. Although truncation diminishes the affinity of the enzyme for both inhibitors, the nitro derivative binds 1.7 kcal/mol more tightly than the dicarboxylate, in reasonable agreement with the calculations. Significantly, substitution of the C10 carboxylate with a nitro group also enhances the selectivity of inhibition of BsCM relative to a chorismate mutase from Escherichia coli (EcCM), which has a completely different fold and binding pocket, by 10-fold. These results experimentally verify the utility of charge optimization methods for improving interactions between proteins and low-molecular weight ligands.

Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor. Publishing Authors By Initials

A Mandal,D Hilvert,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research

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Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of the American Chemical Society

VOLUME: 125

Page Numbers: 5598-9

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 0002-7863

DAY: 14

MONTH: May

YEAR: 2003

Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor. Information

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LANGUAGE: eng

NlmUniqueID: 7503056

Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor. Keywords Mesh Terms:

KEYWORDS: Structure-Activity Relationship

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor. Information

Substance Name: Chorismate Mutase

Registry Number: EC 5.4.99.5

Grant and Affiliation Information for Charge optimization increases the potency and selectivity of a chorismate mutase inhibitor.

AFFILIATION: Laboratorium für Organische Chemie, Swiss Federal Institute of Technology, ETH Hönggerberg, CH-8093 Zürich, Switzerland.

Country: United States

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MEDLINETA: J Am Chem Soc

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