Case Study 2
PKM2 Inhibitor Identification via Virtual Screening and Co-crystal Structure Determination
A hallmark of cancer cells and tumor genesis is metabolic reprogramming, known as the Walburg effect. Pyruvate kinase muscle isozyme 2 (PKM2) catalyzes the last rate-limiting step in aerobic glycolysis and serves as a transcriptional co-activator for the expression of PDL-1. Scientists have pursued design of PKM2 inhibitors and PKM2 activators for potential therapeutic use.
More than one hundred million commercially available compounds can be applied from the ZINC structural libraries for virtual screening. After building up a structure model of PKM2 kinase, we virtually screened million lead-like using DOCK software. 30 high- ranking compounds were selected and purchased for testing. 5 of which showed good activity. IC50 potency of one compound (SBD-1006) reached 3uM and was identified as an allosteric inhibitor in co-crystal structure. The project was completed from virtual screen to co-crystal in less than four weeks.
Figure 1: PKM2 crystal structure
Figure 2: Co-crystal structure of PKM2 complexed