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

Le résumé fourni par la source

Glycogen synthase kinase-3beta (GSK-3beta) 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-3beta inhibitors and inactive compounds using FlexX, FlexX-Pharm, and FlexE. The maximal enrichment factor (EF = 28) suggests that our protocol identifies potential GSK-3beta inhibitors effectively from large compound collections. The effectiveness of our screening protocol was further investigated by comparative experimental and virtual high-throughput screens (HTSs) 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-3beta-based library focusing. Head-to-head comparison of true/false positives and negatives revealed the two approaches to be complementary rather than competitive.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.