ABSTRACT
Pyruvate dehydrogenase complex (PDC) is one of the largest enzyme complexes in mammals. It regulates the decarboxylation of pyruvate, a key step in metabolism. It depletes the carbohydrate reserves in the body. 98To regulate this enzyme, there is another enzyme, pyruvate dehydrogenase kinase (PDHK), which phosphorylates PDC, rendering it inactive. In turn, too much activity of this enzyme reduces metabolism, leading to diseases like diabetes. Therefore, there needs to be a delicate balance between the two enzymes and one needs to inhibit PDHK under some conditions in order to activate PDC. PDHK is actually an enzyme of four types named PDHK1, PDHK2, PDHK3 and PDHK4, all of which have similar amino acid sequences, yet differ in their activities and tissue distribution. Of these, PDHK2 is the most widely distributed in mammalian tissues, and we have focused on this in our work. This chapter describes our work on finding inhibitors of this enzyme. Pyruvate is the most obvious inhibitor of this enzyme, since it is the substrate of PDC. Another similar small molecule is dichloroacetate (DCA), which has proven effective for controlling cancer, but is toxic in itself. Starting from the coordinates of the DCAPDHK2 complex available in the protein data bank, we explored the interactions within this complex. Using drug databases, we looked for similar non-toxic molecules that could dock similarly into the DCA binding site, but could not find any suitable molecule. Since pyruvate also binds into the same site, we also performed virtual screening to find molecules similar to pyruvate, and found some candidates, which were experimentally found to be more potent than DCA without the toxicity. We continued looking for more potent inhibitors based on different strategies, which are described in this chapter.
