Discovery of novel class 1 phosphatidylinositide 3-kinases (PI3K) fragment inhibitors through structure-based virtual screening

Fabrizio Giordanetto; Bengt Kull; Anita Dellsén

doi:10.1016/j.bmcl.2010.11.087

Discovery of novel class 1 phosphatidylinositide 3-kinases (PI3K) fragment inhibitors through structure-based virtual screening

Bioorg Med Chem Lett. 2011 Jan 15;21(2):829-35. doi: 10.1016/j.bmcl.2010.11.087. Epub 2010 Nov 24.

Authors

Fabrizio Giordanetto¹, Bengt Kull, Anita Dellsén

Affiliation

¹ Lead Generation, AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. fabrizio.giordanetto@astrazeneca.com

PMID: 21169017
DOI: 10.1016/j.bmcl.2010.11.087

Abstract

The discovery of ligand efficient and lipophilicity efficient fragment inhibitors of class 1 phosphatidylinositide 3-kinases (PI3K) is reported. A fragment version of the AstraZeneca compound bank was docked to a homology model of the PI3K p110β isoform. Interaction-based scoring of the predicted binding poses served to further prioritise the virtual fragment hits. Experimental screening confirmed potency for a total of 18 fragment inhibitors, belonging to five different structural classes.

MeSH terms

Binding Sites
Drug Design*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Humans
Ligands
Models, Molecular
Phosphatidylinositol 3-Kinase / chemistry
Phosphatidylinositol 3-Kinase / metabolism*
Phosphoinositide-3 Kinase Inhibitors*
Protein Binding
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Ligands
Phosphoinositide-3 Kinase Inhibitors
Phosphatidylinositol 3-Kinase