Ligand Discovery for the human monocarboxylate transporter 1 (MCT1) in an openoutward conformation by virtual screening on ZINC’s FDA-approved drugs

Monocarboxylate transporters (MCTs), encoded by the solute carrier 16 (SLC16) gene family, are a 14-member group of membrane transporters facilitating the displacement of monocarboxylates like pyruvate,lactate, ketone bodies, short-chain fatty acids, and thyroid hormones. The extracellular transport of lactateoccurs mainly by MCT4 and intracellular uptake of lactate is mediated by MCT1, being a proton-dependentprocess involved in the regulation of intracellular pH. It has been shown that overexpression of MCT4 andMCT1 is associated with the development of a variety of malignancies including breast, stomach, lymphoma,brain, lung, skin, and soft tissue cancers. In the tumor microenvironment, differences in cancer cells’ accessto nutrients and oxygen modify cellular metabolism. Cancer cells in a hypoxic state turn to glycolyticmetabolism to continue their survival and proliferation, producing large amounts of lactate inside the cell,which must be transported out of the cell via MCT4. Conversely, oxidative cancerous cells express MCT1 toenter excess lactate, using it as the preferred fuel instead of glucose. This process, called "metabolicsymbiosis" can be targeted as a potential treatment for a variety of cancers. MCT1 inhibition in oxidativecells increases the rate of glucose consumption, causing glycolytic cell death due to glucose deficiency andacidification of their cytosol. In this study, a structure-based virtual screening was performed using the MCT1atomic coordinates (in outward-open conformation) downloaded from protein data bank (PDB) with a codeof 6LYY, and 1778 FDA-approved drugs downloaded from the ZINC database. "FAF-drugs4" webserverand "Open Babel" software were used to remove PAINS compounds and ligand preparation, respectively.Molecular docking calculations were done using "Autodock Vina", "Molegro Virtual Docker" and "DOCK6"programs. The ligands that showed high binding energy were visually analyzed and were introduced forfurther studies.

کلیدواژه های Ligand Discovery for the human monocarboxylate transporter 1 (MCT1) in an openoutward conformation by virtual screening on ZINC’s FDA-approved drugs:

Monocarboxylate transporter1 ، Virtual screening ، Chemical inhibitors ، Cancer