Ligand Discovery for the human monocarboxylate transporter ۱ (MCT۱) in an openoutward conformation by virtual screening on ZINC’s FDA-approved drugs

Monocarboxylate transporters (MCTs), encoded by the solute carrier ۱۶ (SLC۱۶) gene family, are a ۱۴-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 MCT۴ and intracellular uptake of lactate is mediated by MCT۱, being a proton-dependentprocess involved in the regulation of intracellular pH. It has been shown that overexpression of MCT۴ andMCT۱ 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 MCT۴. Conversely, oxidative cancerous cells express MCT۱ 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. MCT۱ 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 MCT۱atomic coordinates (in outward-open conformation) downloaded from protein data bank (PDB) with a codeof ۶LYY, and ۱۷۷۸ FDA-approved drugs downloaded from the ZINC database. "FAF-drugs۴" 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 "DOCK۶"programs. The ligands that showed high binding energy were visually analyzed and were introduced forfurther studies.

کلیدواژه ها:

Monocarboxylate transporter۱ ، Virtual screening ، Chemical inhibitors ، Cancer