Alzheimer's and Parkinson's Disease Novel Therapeutic Target: The Mitochondrial Pyruvate Carrier - Ligand Docking to Screen Natural Compounds Related to Classic Inhibitors

摘要

Thiazolidinedione (TZD) drugs (Takeda Pharmaceuticals and Metabolic Solutions Development Company) targeting inhibition of the mitochondrial pyruvate carrier (MPC) are currently being tested in clinical trials to prevent progression into mild cognitive impairment of Alzheimer's disease (AD) or in the pipeline to prevent neurodegeneration in Parkinson's disease (PD). These have Ki values in the µM range. This study was focused on identifying candidate drug precursors of the natural cinnamic acid products that might have good bioavailability in the nM ranges forming covalent thiol bonds with targets. In silico protein homology modeling and ligand docking has demonstrated that binding cysteine residues within the transport channel is a key part of the inhibitory mechanism. These are covalent thiohemiacetal bonds with the alpha-carbon, carboxylate group, off a phenol ring. Like the classic MPC inhibitors, these natural derivatives of hydroxycinnamic acid have a conjugated pi-system used to form thiol bonds with the cysteine residue via Michael addition.