Virtual screening and biochemical evaluation to identify new inhibitors of mammalian target of rapamycin (mTOR)

Bioorg Med Chem Lett. 2014 Feb 1;24(3):835-8. doi: 10.1016/j.bmcl.2013.12.081. Epub 2013 Dec 27.

Abstract

Mammalian target of rapamycin (mTOR) is a promising target for the development of anticancer medicines. Here, we report the first example for a successful application of the structure-based virtual screening to identify new mTOR inhibitors. Using the scoring function improved by implementing the ligand solvation effects on protein-ligand association, six novel mTOR inhibitors are found with IC50 values ranging from 8 to 60 μM. Because these new inhibitors are also computationally screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further development by structure-activity relationship studies to optimize the inhibitory and anticancer activities. Structural features relevant to the stabilization of the inhibitors in the ATP-binding site of mTOR are addressed in detail.

Keywords: Anticancer agents; Docking; Kinase inhibitor; Virtual screening; mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Computer Simulation*
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Models, Molecular
  • Protein Binding / drug effects
  • Protein Stability / drug effects
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • MTOR protein, human
  • TOR Serine-Threonine Kinases