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

Biomedicines

Lamees Hegazy¹  Sophia Kchouk¹  Christopher Kaiho¹  Bahaa Elgendy¹  Kyle S. McCommis²  Lauren E. Gill²  Kelly D. Pyles²  Brian N. Finck³ 

[1] Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences & Pharmacy, St. Louis, MO 63110, USA;Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA;Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;

关键词: mitochondrial pyruvate carrier;    homology modeling;    mutagenesis;    pharmacophore modeling;    virtual screening;   

DOI  :  10.3390/biomedicines10020365

来源: DOAJ

【 摘 要 】

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 IC₅₀ 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.

【 授权许可】

Unknown