Pyruvate kinase (PK) is an important enzyme in the glycolytic pathway that catalyzes the conversion of phosphoenolpyruvate to pyruvate. One of the isoforms, PKM2, has been shown to have an important role in cancer cell metabolism and growth. As a result, there has been interest in developing inhibitors of this enzyme. We utilized a structure-based design approach to identify novel inhibitors of PKM2. Our design strategy started with the crystal structure of PKM2 with the bound ligand, FBP. We developed a docking model and analyzed the interaction of several known inhibitors, which allowed us to propose a modification that would presumably interact better with the binding site. This modified designed was used as a reference structure in a two-stage similarity search of the NIH Pubchem. In the first stage, there were approximately 39,000 structures identified and this was reduced to 1,314 in the second stage. We identified several compounds having high scores and consistent binding modes, which led to the selection of two cores. After proposing a viable synthesis, virtual libraries were created for each of those cores and then evaluated in the docking model. Workflow software was utilized to process the docking scores, filter by ADME properties, and check for a match to a 3D query based on the binding site. Three novel compounds were initially synthesized and one was found to have an IC50 on a similar scale to the known inhibitor. In an effort to improve on the design of these and other novel inhibitors, we identified the need to incorporate protein flexibility in the docking model. We will report on the design, synthesis, and testing of these compounds for inhibition of PK activity.

Structure-based drug design of pyruvate kinase inhibitors

246th National Meeting (2013)

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