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

Introduction

The 3-carbon metabolite, pyruvate, is a major substrate for energy production in the mitochondrion where it is converted into acetyl-coenzyme A by the pyruvate dehydrogenase complex. In 2012, a family of mitochondrial pyruvate carrier (MPC) membrane proteins were characterized (Herzig et al., 2012). These transporters were shown to carry pyruvate across the inner mitochondrial membrane. As a novel drug target, inhibition of the MPCs by thiazolidinedione (TZD) (Divakaruni et al., 2013) drugs is being tested for the prevention of mild cognitive impairment from Alzheimer’s disease and the prevention of neurodegeneration from Parkinson’s disease (Divakarini et al., 2017; Ghosh et al., 2016; Shah et al., 2014); see also a companion paper in this issue (Phelix, Bourdon, Dugan, Villareal, & Perry, 2017). Since the standard control MPC inhibitors, used in validation studies of the novel MPC inhibitors, are cyano-derivatives of a synthetic form of cinnamic acid, we were curious why no one has ever tested any of the natural cinnamic acid compounds for MPC inhibition. Relative to Alzheimer’s disease we are also interested in the numerous natural derivatives that have potent anti-oxidant properties, since a key research focus has been on oxidative stress as the earliest measurable events in progression of this disease (Hammack, Perry, LeBaron, Villareal, & Phelix, 2015; Nunomura et al., 2001; Sayre, Smith, & Perry, 2001). Interestingly, caffeic acid phenethyl ester (2-phenylethyl (2E)-3-(3, 4-dihydroxyphenyl) acrylate, CAPE; also, a natural product from cinnamic acid) has been shown to prevent dementia in rats that had received intracerebroventricular streptozotocin (Kumar, Kaur, & Bansal, 2017).