{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Hegazy L"],"funding":["NCATS NIH HHS","NIDDK NIH HHS","National Institutes of Health","NIH HHS"],"pagination":["365"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8962382"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(2)"],"pubmed_abstract":["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<sub>50</sub> 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."],"journal":["Biomedicines"],"pubmed_title":["Identification of Novel Mitochondrial Pyruvate Carrier Inhibitors by Homology Modeling and Pharmacophore-Based Virtual Screening."],"pmcid":["PMC8962382"],"funding_grant_id":["UL1 TR002345","R00 HL136658","R01 DK104735","P30 DK056341"],"pubmed_authors":["Finck BN","McCommis KS","Kchouk S","Pyles KD","Elgendy B","Kaiho C","Gill LE","Hegazy L"],"additional_accession":[]},"is_claimable":false,"name":"Identification of Novel Mitochondrial Pyruvate Carrier Inhibitors by Homology Modeling and Pharmacophore-Based Virtual Screening.","description":"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<sub>50</sub> 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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Feb","modification":"2026-04-08T17:58:54.873Z","creation":"2025-04-06T21:48:33.995Z"},"accession":"S-EPMC8962382","cross_references":{"pubmed":["35203575"],"doi":["10.3390/biomedicines10020365"]}}