Abstract
Transition state analogues of PNP, the Immucillins and DADMe-Immucillins, were designed to match transition state features of bovine and human PNPs, respectively. The inhibitors with or without the hydroxyl and hydroxymethyl groups of the substrate demonstrate that inhibitor geometry mimicking that of the transition state confers binding affinity discrimination. This finding is remarkable since crystallographic analysis indicates complete conservation of active site residues and contacts to ligands in human and bovine PNPs.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Arsenates / chemistry
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Cattle
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Enzyme Inhibitors* / chemistry
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Enzyme Inhibitors* / pharmacology
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Erythrocytes / enzymology
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Humans
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Mice
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Molecular Structure
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Protein Binding
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Purine Nucleosides / chemistry
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Purine-Nucleoside Phosphorylase / antagonists & inhibitors
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Purine-Nucleoside Phosphorylase / chemistry*
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Pyrimidinones / chemistry
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Pyrrolidines / chemistry
Substances
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Arsenates
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DADMe-immucillin H
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Enzyme Inhibitors
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Purine Nucleosides
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Pyrimidinones
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Pyrrolidines
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forodesine
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Purine-Nucleoside Phosphorylase