Farnesyl diphosphate synthase inhibitors from in silico screening

Steffen Lindert, Wei Zhu, Yi Liang Liu, Ran Pang, Eric Oldfield, J. Andrew Mccammon

Research output: Contribution to journalArticlepeer-review

Abstract

The relaxed complex scheme is an in silico drug screening method that accounts for receptor flexibility using molecular dynamics simulations. Here, we used this approach combined with similarity searches and experimental inhibition assays to identify several low micromolar, non-bisphosphonate inhibitors, bisamidines, of farnesyl diphosphate synthase (FPPS), an enzyme targeted by some anticancer and antimicrobial agents and for the treatment of bone resorption diseases. This novel class of farnesyl diphosphate synthase inhibitors have more drug-like properties than existing bisphosphonate inhibitors, making them interesting pharmaceutical leads. The relaxed complex scheme is an in silico drug screening method that accounts for receptor flexibility using molecular dynamics simulations. Here, we used this approach combined with similarity searches to identify several low micromolar, non-bisphosphonate inhibitors, bisamidines, of farnesyl diphosphate synthase (FPPS), an enzyme targeted by some anticancer and antimicrobial agents and for the treatment of bone resorption diseases. This novel class of FPPS inhibitors have more drug-like properties than existing bisphosphonate inhibitors, making them interesting pharmaceutical leads.

Original languageEnglish (US)
Pages (from-to)742-748
Number of pages7
JournalChemical Biology and Drug Design
Volume81
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Drug discovery
  • Molecular modeling
  • Virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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