Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site

Cell Chem Biol. 2018 Feb 15;25(2):185-193.e5. doi: 10.1016/j.chembiol.2017.11.010. Epub 2017 Dec 21.

Abstract

The bifunctional farnesyl/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key branchpoint enzyme in isoprenoid biosynthesis in Plasmodium falciparum (malaria) parasites. PfFPPS/GGPPS is a validated, high-priority antimalarial drug target. Unfortunately, current bisphosphonate drugs that inhibit FPPS and GGPPS enzymes by acting as a diphosphate substrate analog show poor bioavailability and selectivity for PfFPPS/GGPPS. We identified a new non-bisphosphonate compound, MMV019313, which is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes of inhibition. Molecular docking indicated that MMV019313 did not bind previously characterized substrate sites in PfFPPS/GGPPS. Our finding uncovers a new, selective small-molecule binding site in this important antimalarial drug target with superior druggability compared with the known inhibitor site and sets the stage for the development of Plasmodium-specific FPPS/GGPPS inhibitors.

Keywords: drug discovery; farnesyl/geranylgeranyl diphosphate synthase; high-throughput screening; malaria; non-bisphosphonate inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Farnesyltranstransferase / metabolism
  • Geranyltranstransferase / antagonists & inhibitors*
  • Geranyltranstransferase / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Plasmodium falciparum / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*

Substances

  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Geranyltranstransferase
  • Farnesyltranstransferase