Identification of Novel Mitochondrial Pyruvate Carrier Inhibitors by Homology Modeling and Pharmacophore-Based Virtual Screening

The mitochondrial pyruvate carrier (MPC) is an inner-mitochondrial membrane protein complex that has emerged as a drug target for treating a variety of human conditions. A heterodimer of two proteins, MPC1 and MPC2, comprises the functional MPC complex in higher organisms; however, the structure of...

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Bibliographic Details
Published in:Biomedicines 2022-02, Vol.10 (2), p.365
Main Authors: Hegazy, Lamees, Gill, Lauren E, Pyles, Kelly D, Kaiho, Christopher, Kchouk, Sophia, Finck, Brian N, McCommis, Kyle S, Elgendy, Bahaa
Format: Article
Language:English
Subjects:
Amino acids
Binding sites
Bioavailability
Homology
homology modeling
Hypotheses
Ligands
Membrane proteins
Metabolism
Mitochondria
mitochondrial pyruvate carrier
Mutagenesis
pharmacophore modeling
Proteins
Pyruvic acid
Structure-function relationships
Therapeutic targets
virtual screening
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Summary:The mitochondrial pyruvate carrier (MPC) is an inner-mitochondrial membrane protein complex that has emerged as a drug target for treating a variety of human conditions. A heterodimer of two proteins, MPC1 and MPC2, comprises the functional MPC complex in higher organisms; however, the structure of this complex, including the critical residues that mediate binding of pyruvate and inhibitors, remain to be determined. Using homology modeling, we identified a putative substrate-binding cavity in the MPC dimer. Three amino acid residues (Phe66 (MPC1) and Asn100 and Lys49 (MPC2)) were validated by mutagenesis experiments to be important for substrate and inhibitor binding. Using this information, we developed a pharmacophore model and then performed a virtual screen of a chemical library. We identified five new non-indole MPC inhibitors, four with IC values in the nanomolar range that were up to 7-fold more potent than the canonical inhibitor UK-5099. These novel compounds possess drug-like properties and complied with Lipinski's Rule of Five. They are predicted to have good aqueous solubility, oral bioavailability, and metabolic stability. Collectively, these studies provide important information about the structure-function relationships of the MPC complex and for future drug discovery efforts targeting the MPC.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines10020365