Structure-based virtual screening of FDA-approved compounds to find potential inhibitors for human monocarboxylate transporter ۱ in an open-inward conformation

Owing to the high rate of glycolysis, increased access to glucose is necessary for cancer cells to survive andproliferation. To adapt to the changes in the tumor microenvironment, two groups of cells develop: glycolyticand oxidative cancer cells. Altered metabolism and increased glucose consumption in the glycolytic cellslead to increased intracellular lactate levels, which have to be removed from those cells and absorbed by theoxidative ones. Lactate is transported by a number of monocarboxylate transporters (MCT), which has beenidentified as a family of ۱۴ members, ranging from MCT۱ to MCT۱۴. The monocarboxylate transporter ۱(MCT۱) catalyzes the movement of monocarboxylates such as lactate and pyruvate across the plasmamembrane of mammalian cells. The overexpression of MCT۱ has been reported in several cancers includinglung, colon, brain, skin and lymphoma cancers. Therefore, inhibition of MCT۱ holds great promise for cancertreatment. In the present study, we screened the FDA-approved compounds of the Zinc Database usingstructure-based virtual screening methods to find effective compounds for inhibition of the MCT۱ transporterin an open-inward conformation. To this end, the resolved structure of MCT۱ was downloaded from RCSB(PDB ID: ۷CKO). To prepare the chemical library, FAF-drugs۴ was applied on FDA-approved subset ofZINC to remove compounds having more than ۱۰ rotatable bonds and PAINS. Next, the clean library wasenergy minimized using Mmff۹۴ force field. In follow, we docked the resultant library against MCT۱ usinga funnel-like pattern by Autodock Vina, Molegro Virtual Docker, and DOCK۶. The compounds obtainedfrom this step were studied for further investigation.

کلیدواژه ها:

Monocarboxylate Transporter۱ ، Virtual screening ، inhibitors ، Cancer