MSDC-0160 and MSDC-0602 Binding with Human Mitochondrial Pyruvate Carrier (MPC) 1 and 2 Heterodimer: PPARγ Activating and Sparing TZDs as Therapeutics

The mitochondrial pyruvate carrier (MPC) is a novel target for therapeutic drugs to treat Alzheimer's and Parkinson's disease, diabetes mellitus, and non-alcoholic steatohepatitis (NASH). Metabolic Solutions Development Company (MSDC) has two thiazolidinediones, MSDC-0160 and MSDC-0602, in the pipeline. This report describes results for a MPC1/2 heterodimer homology model. The FASTA sequences for MPC1 and MPC2 were accessed from UniProt and submitted to RaptorX, resulting in best candidate monomeric “protein data base” files for each. One mutant form of MPC1, L36I, was also processed. These were submitted to PyDock to generate best candidate MPC1/2 heterodimer models that were used for ligand docking analyses with AutoDock Vina and “Rosetta Online Server that Includes Everyone” (ROSIE). Multiple binding sites for pyruvate and both drugs were found on both MPC1 and MPC2 subunits with drugs having nearly double the affinity in each case except the intermediate and open-in states for the L36I mutant transporter.