Comparative Virtual and Experimental High-Throughput Screening for Glycogen Synthase Kinase-3b Inhibitors

Abstract
Glycogen synthase kinase-3b is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes.

As an initial step of our lead discovery program we developed a virtual screen to discriminate known GSK-3b inhibitors and inactive compounds using FlexX, FlexX-Pharm and FlexE.

The maximal enrichment factor (EF=28) suggests that our protocol identifies potential GSK-3b inhibitors effectively from large compound collections. The effectiveness of our screening protocol was further investigated by a comparative experimental and virtual high-throughput screens performed for the same subset of our corporate library.

Enrichment factors, the significantly higher hit rate of virtual screening (12.9%) than that of the HTS (0.55%) and also the comparison of active clusters suggest that our virtual screening protocol is an effective tool in GSK-3b -based library focusing. Head-to-head comparison of true/false positives and negatives, revealed the two approaches to be complementary rather than competitive.