pmid: 31752556,   nlmid 101150203,  doi:10.1080/14756366.2019.1693704

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


Martínez de Iturrate, Paula Sebastián-Pérez, Victor Nácher-Vázquez, Montserrat Tremper, Catherine S Smirlis, Despina Martín, Julio Martínez, Ana Campillo, Nuria E Rivas, Luis Gil, Carmen

Vol. 35, Issue 35, Dec.2020

Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem),  ISSN 1475-6374

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-3? 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.


MESH Headings


Article Keywords

GSK-3 | Leishbox | Leishmania | molecular modelling |


Chemical

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