A guanidinium-based inhibitor of a type I isopentenyl diphosphate isomerase

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127577. doi: 10.1016/j.bmcl.2020.127577. Epub 2020 Sep 23.

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 Ki 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.

Keywords: Allylic diphosphate; Guanidinium; Inhibitor; Isomerase; Prenyltransferase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon-Carbon Double Bond Isomerases / antagonists & inhibitors*
  • Carbon-Carbon Double Bond Isomerases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / enzymology
  • Geranyltranstransferase / antagonists & inhibitors
  • Geranyltranstransferase / metabolism
  • Guanidine / chemical synthesis
  • Guanidine / chemistry
  • Guanidine / pharmacology*
  • Hemiterpenes / antagonists & inhibitors*
  • Hemiterpenes / metabolism
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Hemiterpenes
  • Geranyltranstransferase
  • Carbon-Carbon Double Bond Isomerases
  • isopentenyldiphosphate delta-isomerase
  • Guanidine