Phosphoinositide-3-kinase (PI3K) inhibitors: identification of new scaffolds using virtual screening.
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.
Frédérick
Raphaël
R
Auckland Cancer Society Research Centre (ACSRC), School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand. raphael.frederick@gmail.com
Mawson
Claire
C
Kendall
Jackie D
JD
Chaussade
Claire
C
Rewcastle
Gordon W
GW
Shepherd
Peter R
PR
Denny
William A
WA
D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D055808:Drug Discovery; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors