MSDC-0160 and MSDC-0602 Binding with Human Mitochondrial Pyruvate Carrier (MPC) 1 and 2 Heterodimer

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.

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MSDC-0160 and MSDC-0602 Binding with Human Mitochondrial Pyruvate Carrier (MPC) 1 and 2 Heterodimer

Research Anthology on Diagnosing and Treating Neurocognitive Disorders ◽

10.4018/978-1-7998-3441-0.ch022 ◽

2021 ◽

pp. 427-455

Author(s):

Clyde F. Phelix ◽

Allen K. Bourdon ◽

Jason L Dugan ◽

Greg Villareal ◽

George Perry

Keyword(s):

Diabetes Mellitus ◽

Data Base ◽

Homology Model ◽

Ligand Docking ◽

Mutant Form ◽

Therapeutic Drugs ◽

Multiple Binding Sites ◽

Mitochondrial Pyruvate Carrier ◽

Multiple Binding ◽

Novel Target

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Faculty Opinions recommendation of Multiple binding sites for the general anesthetic isoflurane identified in the nicotinic acetylcholine receptor transmembrane domain.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5804956.5786054 ◽

2010 ◽

Author(s):

Edward Bertaccini

Keyword(s):

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Binding Sites ◽

Transmembrane Domain ◽

General Anesthetic ◽

Nicotinic Acetylcholine ◽

Multiple Binding Sites ◽

Multiple Binding

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NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666191011095341 ◽

2019 ◽

Vol 19 (24) ◽

pp. 2239-2253 ◽

Cited By ~ 2

Author(s):

Paul J. Goldsmith

Keyword(s):

Binding Sites ◽

Receptor Activation ◽

Research Area ◽

Allosteric Modulators ◽

Nonselective Cation Channels ◽

Multiple Binding Sites ◽

Multiple Binding ◽

Excitatory Neurotransmission ◽

Psychiatric Conditions ◽

High Level

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

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Effects of Multiple Binding Sites on Studies of Hydrogen Bonding between Nitroxide Radicals and Solvent Molecules

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19930047 ◽

1993 ◽

Vol 58 (1) ◽

pp. 47-52 ◽

Cited By ~ 2

Author(s):

Imad Al-Bala'a ◽

Richard D. Bates

Keyword(s):

Hydrogen Bonding ◽

Magnetic Resonance ◽

Binding Site ◽

Binding Sites ◽

Hyperfine Coupling Constant ◽

Hydrogen Donor ◽

Complex Formation Constants ◽

Multiple Binding Sites ◽

Multiple Binding ◽

Solvent Molecules

The role of more than one binding site on a nitroxide free radical in magnetic resonance determinations of the properties of the complex formed with a hydrogen donor is examined. The expression that relates observed hyperfine couplings in EPR spectra to complex formation constants and concentrations of each species in solution becomes much more complex when multiple binding sites are present, but reduces to a simpler form when binding at the two sites occurs independently and the binding at the non-nitroxide site does not produce significant differences in the hyperfine coupling constant in the complexed radical. Effects on studies of hydrogen bonding between multiple binding site nitroxides and hydrogen donor solvent molecules by other magnetic resonance methods are potentially more extreme.

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