Pharmacophore-Based Virtual Screening Toward the Discovery of Novel GLUT1 Inhibitors

Abstract

Glucose transporter 1 (GLUT1) plays an important role in the transport of glucose into cells. Studies found that GLUT1 is highly expressed in a variety of tumor cells, and it’s the rate-limiting transporter for tumor cells to uptake glucose, meaning that GLUT1 is a potential target for tumor treatment. Thus, the inhibition of GLUT1 by novel small compounds to lower glucose levels for cancer cells has become an emerging strategy. In this study, potential GLUT1 inhibitors were discovered by pharmacophore-based high-throughput virtual screening. First, 96 GLUT1 inhibitors were used to establish common pharmacophore hypotheses. The best pharmacophore model ADHRRR_1 was used to screen the ZINC database. Then, ADMET was launched to predict the pharmacokinetics of hit compounds from virtual screening. After that, the standard docking and precise docking were employed to dock these compounds with 4PYP protein; five molecules were selected as candidates of GLUT1 inhibitors for further analysis. Molecular Dynamic (MD) simulations and Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) method were applied to evaluate the binding stability and affinity of the five protein–ligand composites. Finally, Zinc000068152777 and Zinc000141918576 with lower docking scores and binding free energy emerged as the potential GLUT1 inhibitors. Taken together, these results in our study may provide valuable information for cancer therapeutics by disturbing the energy metabolism of tumors.