Towards discovery of new leishmanicidal scaffolds able to inhibit Leishmania GSK-3

J Enzyme Inhib Med Chem. 2020 Dec;35(1):199-210. doi: 10.1080/14756366.2019.1693704.

Abstract

Previous reports have validated the glycogen synthase kinase-3 (GSK-3) as a druggable target against the human protozoan parasite Leishmania. This prompted us to search for new leishmanicidal scaffolds as inhibitors of this enzyme from our in-house library of human GSK-3β inhibitors, as well as from the Leishbox collection of leishmanicidal compounds developed by GlaxoSmithKline. As a result, new leishmanicidal inhibitors acting on Leishmania GSK-3 at micromolar concentrations were found. These inhibitors belong to six different chemical classes (thiadiazolidindione, halomethylketone, maleimide, benzoimidazole, N-phenylpyrimidine-2-amine and oxadiazole). In addition, the binding mode of the most active compounds into Leishmania GSK-3 was approached using computational tools. On the whole, we have uncovered new chemical scaffolds with an appealing prospective in the development and use of Leishmania GSK-3 inhibitors against this infectious protozoan.

Keywords: GSK-3; Leishbox; Leishmania; molecular modelling.

MeSH terms

  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Leishmania / cytology
  • Leishmania / drug effects*
  • Leishmania / enzymology
  • Molecular Docking Simulation
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antiprotozoal Agents
  • Protein Kinase Inhibitors
  • Glycogen Synthase Kinase 3

Grants and funding

Funding from MINECO [Grant SAF2015-65740-R], Instituto de Salud Carlos III RETICS programme RICET [RD16/0027/0010] with associated FEDER funds and MECD [Grant FPU15/1465 to V. S.-P.] is acknowledged. P. M. acknowledges the contract from the European Social Fund (Youth Employment Initiative) and FEDER funds.