Farnesyl diphosphate synthase inhibitors from in silico screening.

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.

• Authors: Steffen Lindert, Wei Zhu, Yi-Liang Liu, Ran Pang, Eric Oldfield, J Andrew McCammon
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 81 Issue 6 Pg. 742-8 (Jun 2013) ISSN: 1747-0285 [Electronic] England
• PMID: 23421555 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2013 John Wiley & Sons A/S.

Chemical References

• Enzyme Inhibitors
• Furans
• bisamidine
• Geranyltranstransferase

Topics

• Allosteric Site
• Area Under Curve
• Crystallography, X-Ray
• Enzyme Inhibitors (chemistry, metabolism)
• Furans (chemistry, metabolism)
• Geranyltranstransferase (antagonists & inhibitors, metabolism)
• Molecular Docking Simulation
• Protein Binding
• Protein Structure, Tertiary
• ROC Curve