Abstract
Protein kinase B (PKB/AKT) is a promising and attractive therapeutic target in anticancer drug development. Herein, we report the findings of virtual screening for novel ATP-competitive inhibitors of AKT-2 using 2D- and 3D-similarity searching and sequential molecular docking with two crystal structures of AKT-2. Our multistep approach led to the identification of a low micromolar AKT-2 inhibitor (IC(50)=1.5 microM) with a novel scaffold. The experimentally validated inhibitor represents the starting point for an optimization program.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Cell Line, Tumor
-
Computer Simulation
-
Crystallography, X-Ray
-
Databases, Factual
-
Drug Discovery
-
Humans
-
Protein Isoforms / antagonists & inhibitors
-
Protein Isoforms / metabolism
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacology
-
Protein Structure, Tertiary
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-akt / metabolism
-
Structure-Activity Relationship
Substances
-
Protein Isoforms
-
Protein Kinase Inhibitors
-
Proto-Oncogene Proteins c-akt