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A guanidinium-based inhibitor of a type I isopentenyl diphosphate isomerase.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Nov 15; Vol. 30 (22), pp. 127577. Date of Electronic Publication: 2020 Sep 23. - Publication Year :
- 2020
-
Abstract
- An inhibitor bearing a phosphinylphosphonate group appended to a guanidinium functionality was designed to inhibit enzymes that generate carbocations from dimethylallyl diphosphate. When tested against human farnesyl diphosphate synthase the inhibitor bound with high micromolar affinity and did not bind more tightly than an isosteric inhibitor lacking the guanidinium functionality. When tested against the Type I isopentenyl diphosphate:dimethylallyl diphosphate isomerase from Escherichia coli, the inhibitor bound with a K <subscript>i</subscript> value of 120 nM, which was 400 times greater than its isosteric counterpart. This strategy of inhibition was much more effective with an enzyme that generates a carbocation that is not stabilized by both resonance and ion pairing, presumably because there is more evolutionary pressure on the enzyme to stabilize the cation.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Carbon-Carbon Double Bond Isomerases metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Escherichia coli enzymology
Geranyltranstransferase antagonists & inhibitors
Geranyltranstransferase metabolism
Guanidine chemical synthesis
Guanidine chemistry
Hemiterpenes metabolism
Humans
Molecular Structure
Structure-Activity Relationship
Carbon-Carbon Double Bond Isomerases antagonists & inhibitors
Enzyme Inhibitors pharmacology
Guanidine pharmacology
Hemiterpenes antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 30
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 32979487
- Full Text :
- https://doi.org/10.1016/j.bmcl.2020.127577