Screening of Large Neutral Amino Acid Transporter 1 (LAT-1) Inhibitors Using FOOD-lib Library and Lipinski's Rule

Screening of Large Neutral Amino Acid Transporter 1 (LAT-1) Inhibitors Using FOOD-lib Library and Lipinski's Rule
Fahimeh Haghshenas,¹ Farshad Qalekhani,^2,* Mahnaz Ghowsi,³
1. Biology Department, Razi University, Kermanshah, Iran
2. Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences (KUMS), Kermanshah, Iran.
3. Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences (KUMS), Kermanshah, Iran.
Introduction: SLC7A5, known as L-type Amino acid Transporter 1 (LAT1), belongs to the APC superfamily and forms a heterodimeric amino acid transporter interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide [1]. LAT1 is a membrane transport protein that preferentially transports branched-chain (valine, leucine and isoleucine) and aromatic (tryptophan, tyrosine) amino acids [2]. LAT1 plays a significant role in the growth and propagation of cancer cells by facilitating the cross-membrane transport of essential nutrients, and is an attractive drug target [3]. Here, we report a structure-based approach to identify chemically diverse and potent inhibitors of LAT1.
Methods: At first, the three-dimensional (3D) structure of the LAT-1 was downloaded from RCSB (PDB ID: 6JMQ/Chain A). In order to virtual screening, a library containing 10997 compounds (FOOD-lib) was used in MTiOpenScreen server. Virtual screening against the LAT-1 was performed by using AutoDock Vina program. Ligands with less than -10 binding energy were selected for subsequent analysis. The molecular structures of ligands were analyzed using SWISSADME server in order to confirm whether the physicochemical properties like molecular weight, hydrogen bond donor, hydrogen bond acceptor, lipophilicity and molar refractivity of ligands follow Lipinski’s rule of five or not. Absorption, distribution, metabolism, and excretion (ADME) each profile of ligand was calculated using pkCSM server. General toxicity, cardiotoxicity (Pred-hERG server) and hepatotoxicity (Vienna LiverTox server) were investigated. Metabolism sites of best ligand to three isoforms i.e. CYP3A4 CYP2D6 and CYP2C9 of cytochrome P450 family of enzymes were predicted utilizing online-based RS-WebPredictor server.
Results: After docking, 12 top ligands were chosen (Energy < -11). Two ligands followed Lipinski’s rule. Toxicity of these two ligands was investigated, and finally, Smilagenone (ZINC000118936408) was found to be non-toxic, and its cytochromes P450 metabolism sites were determined.
Conclusion: Given the role of LAT1 in cancer progression, LAT1 was selected as a drug target. Virtual screening on MtiOpenScreen server identified 12 drug candidates. After pharmacokinetic and pharmacodynamic studies, composition Smilagenone was selected as the lead compound. It is expected Smilagenone will act as an inhibitor and prevent the supply of amino acids to cancer cells, thus impeding the protein synthesis and cellular proliferation. Authors suggest further in vitro and in vivo study with Smilagenone to confirm their anticancer activities and strengthen this finding.
Keywords: AutoDock Vina, Cancer, LAT1, MTiOpenScreen, SLC7A5.