Phosphoinositide-3-kinase (PI3K) inhibitors: identification of new scaffolds using virtual screening

  • Bioorg Med Chem Lett. 2009 Oct 15;19(20):5842-7. doi: 10.1016/j.bmcl.2009.08.087.
Raphaël Frédérick  1 ,  Claire Mawson ,  Jackie D Kendall ,  Claire Chaussade ,  Gordon W Rewcastle ,  Peter R Shepherd ,  William A Denny
Affiliations
  • 1. Auckland Cancer Society Research Centre (ACSRC), School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand. [email protected]
PMID: 19748269 DOI: 10.1016/j.bmcl.2009.08.087
Abstract

In the present work, we used virtual screening (VS) of the ZINC database of 2.5 million compounds to seek new PI3K inhibitory scaffolds. The VS flowchart implemented various filters, including a 3D-database screen, and extensive docking studies, to derive 89 derivatives that were experimentally assayed against the four PI3K isoforms. Seven compounds showed inhibitory activities between 1 and 100 microM, with four being sufficiently potent to constitute potential new scaffolds. The binding conformations of these four were analyzed to provide a rationalization of their activity profile.