Abstract
L-type Amino acid Transporter 1 (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. Several halogen-containing L-phenylalanine-based ligands display high affinity and high selectivity for LAT1; nonetheless, their molecular mechanism of binding remains unclear. In this study, a combined in silico strategy consisting of homology modeling, molecular docking, and Quantum Mechanics-Molecular Mechanics (QM-MM) simulation was applied to elucidate the molecular basis of ligand binding in LAT1. First, a homology model of LAT1 based on the atomic structure of a prokaryotic homolog was constructed. Docking studies using a set of halogenated ligands allowed for deriving a binding hypothesis. Selected docking poses were subjected to QM-MM calculations to investigate the halogen interactions. Collectively, the results highlight the dual nature of the ligand-protein binding mode characterized by backbone hydrogen bond interactions of the amino acid moiety of the ligands and residues I63, S66, G67, F252, G255, as well as hydrophobic interactions of the ligand’s side chains with residues I139, I140, F252, G255, F402, W405. QM-MM optimizations indicated that the electrostatic interactions involving halogens contribute to the binding free energy. Importantly, our results are in good agreement with the recently unraveled cryo-Electron Microscopy structures of LAT1.
Highlights
The availability of experimentally determined high-resolution protein-ligand structures intensely expedites the design and optimization of small molecules during the drug discovery process through elaborative multiparameter ligand optimization
The meta position of the aromatic ring has been described to be most favorable for affinity, as the substituents are believed to interact with a secondary hydrophobic sub-pocket in LAT138
It may be inferred that L-type Amino acid Transporter 1 (LAT1) represents a case of heterogeneous Structure-Activity Relationship (SAR) that is characterized by concurrent existence of different continuous and discontinuous SAR, where SAR continuity is observed within the limits of a structural constraint, i.e., amino acid moiety of the ligands
Summary
The availability of experimentally determined high-resolution protein-ligand structures intensely expedites the design and optimization of small molecules during the drug discovery process through elaborative multiparameter ligand optimization. This knowledge can assist medicinal chemists in optimizing the pharmacokinetic properties of the ligand, without disrupting the important protein-ligand contacts[1,2] It facilitates the elucidation of molecular features involved in ligand-binding, leading, for example, to agonist and antagonist actions of the small molecules[3]. The sequence similarity between target and template proteins plays a crucial role in determining the success of homology modeling and subsequent docking studies[6]. Past studies have highlighted the potential of homology modeling to be used for understanding the transport mechanism[33,35], structure-function relationship[36], and discovery of novel ligands of LAT137. We combine homology modeling, molecular docking, and Quantum Mechanics-Molecular Mechanics (QM-MM) to define a binding hypothesis for the halogenated phenylalanine-based ligands of LAT1. The results from the docking studies were compared with the newly solved cryo-Electron Microscopy (cryo-EM) structures (PDB IDs: 6IRT, 6JMQ) of human LAT1-CD98 complex[12,32]
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