1st International and 10th National Iranian Conference on Bioinformatics

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

Paper ID : 1286-ICB10

Authors:

Mina Barhoon, Hamid Mahdiuni *, Soraya Sajadimajd

Department of Biology, School of Sciences, Razi University, Kermanshah, Iran

Abstract:

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 [1]. The extracellular transport of lactate occurs mainly by MCT4 and intracellular uptake of lactate is mediated by MCT1, being a proton-dependent process involved in the regulation of intracellular pH. It has been shown that overexpression of MCT4 and MCT1 is associated with the development of a variety of malignancies including breast, stomach, lymphoma, brain, lung, skin, and soft tissue cancers [2-4]. In the tumor microenvironment, differences in cancer cells’ access to nutrients and oxygen modify cellular metabolism. Cancer cells in a hypoxic state turn to glycolytic metabolism to continue their survival and proliferation, producing large amounts of lactate inside the cell, which must be transported out of the cell via MCT4 [5]. Conversely, oxidative cancerous cells express MCT1 to enter excess lactate, using it as the preferred fuel instead of glucose. This process, called "metabolic symbiosis" can be targeted as a potential treatment for a variety of cancers. MCT1 inhibition in oxidative cells increases the rate of glucose consumption, causing glycolytic cell death due to glucose deficiency and acidification of their cytosol [6]. In this study, a structure-based virtual screening was performed using the MCT1 atomic coordinates (in outward-open conformation) downloaded from protein data bank (PDB) with a code of 6LYY, and 1778 FDA-approved drugs downloaded from the ZINC database. "FAF-drugs4" webserver and "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 for further studies.

Keywords:

Monocarboxylate transporter1, Virtual screening, Chemical inhibitors, Cancer

Status : Paper Accepted (Poster Presentation)