Design, synthesis and biological evaluation of Pontin ATPase inhibitors through a molecular docking approach

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2512-6. doi: 10.1016/j.bmcl.2014.04.003. Epub 2014 Apr 13.

Abstract

A virtual screening strategy, through molecular docking, for the elaboration of an electronic library of Pontin inhibitors has resulted in the identification of two original scaffolds. The chemical synthesis of four candidates allowed extensive biological evaluations for their anticancer activity. Two compounds displayed an effect on Pontin ATPase activity, and one of them also exhibited a noticeable effect on cell growth. Further biological studies revealed that the most active compound induced apoptotic cell death together with necrosis, this latter effect being likely related to the cellular balance of ATP regulation.

Keywords: ATPase activity; Enzymatic assay; Molecular docking; Pontin; Small-molecule inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Cell Proliferation / drug effects
  • DNA Helicases / antagonists & inhibitors*
  • DNA Helicases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HCT116 Cells
  • HL-60 Cells
  • Humans
  • KB Cells
  • MCF-7 Cells
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • Enzyme Inhibitors
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • RUVBL1 protein, human