• Open Access

Farnesyl Diphosphate Synthase Inhibitors from In Silico Screening

Authors

  • Steffen Lindert,

    Corresponding author
    1. NSF Center for Theoretical Biological Physics, La Jolla, CA, USA
    • Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
    Search for more papers by this author
  • Wei Zhu,

    1. Center for Biophysics & Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
    Search for more papers by this author
  • Yi-Liang Liu,

    1. Center for Biophysics & Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
    Search for more papers by this author
  • Ran Pang,

    1. School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
    Search for more papers by this author
  • Eric Oldfield,

    1. Center for Biophysics & Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
    2. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
    Search for more papers by this author
  • J. Andrew McCammon

    1. Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
    2. NSF Center for Theoretical Biological Physics, La Jolla, CA, USA
    3. Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, USA
    4. Department of Chemistry & Biochemistry, National Biomedical Computation Resource, University of California San Diego, La Jolla, CA, USA
    Search for more papers by this author

Corresponding author: Steffen Lindert, slindert@ucsd.edu

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.

Ancillary