Τίτλος:
A holistic evolutionary and 3d pharmacophore modelling study provides insights into the metabolism, function, and substrate selectivity of the human monocarboxylate transporter 4 (Hmct4)
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4; however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Συγγραφείς:
Papakonstantinou, E.
Vlachakis, D.
Thireou, T.
Vlachoyiannopoulos, P.G.
Eliopoulos, E.
Περιοδικό:
International Journal of Molecular Sciences
Λέξεις-κλειδιά:
antineoplastic agent; lactic acid; monocarboxylate transporter 4; AR C155858; AZD3965; isoprotein; monocarboxylate transporter; muscle protein; phloretin; protein binding; pyrimidinone derivative; quercetin; reserpine; SLC16A4 protein, human; syrosingopine; thiophene derivative; uracil, acidification; Article; cancer cell; cell proliferation; cellular distribution; controlled study; enzyme inhibition; enzyme substrate; evolution; glycolysis; human; molecular model; pharmacophore; phenotype; phylogenetic tree; protein function; protein metabolism; sequence alignment; solid malignant neoplasm; tissue distribution; tumor metabolism; alpha helix; animal; binding site; chemistry; drug design; enzyme specificity; genetics; metabolism; molecular docking; phylogeny; physiology; protein domain; structural homology; transport at the cellular level, Animals; Antineoplastic Agents; Binding Sites; Biological Transport; Drug Design; Glycolysis; Humans; Lactic Acid; Molecular Docking Simulation; Monocarboxylic Acid Transporters; Muscle Proteins; Phloretin; Phylogeny; Protein Binding; Protein Conformation, alpha-Helical; Protein Interaction Domains and Motifs; Protein Isoforms; Pyrimidinones; Quercetin; Reserpine; Structural Homology, Protein; Substrate Specificity; Thiophenes; Uracil
DOI:
10.3390/ijms22062918
