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

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

Allen K. Bourdon (University of Tennessee at Knoxville, Knoxville, Tennessee, United States), Greg Villareal (AL Phahelix Biometrics, Inc., San Antonio, Texas, United States), George Perry (University of Texas at San Antonio, San Antonio, Texas, United States) and Clyde F. Phelix (University of Texas at San Antonio, San Antonio, Texas, United States)
Copyright: © 2017 |Pages: 15
DOI: 10.4018/IJKDB.2017070104
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Abstract

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.
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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).

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