Rigorous sampling of docking poses unveils binding hypothesis for the halogenated ligands of L-type Amino acid Transporter 1 (LAT1)

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.

L-Type amino acid transporter 1 as a target for drug delivery

“…In contrast, as the transporter plays a crucial role in cancer cell growth and survival, a strategy to affect the function and expression of LAT1 in a tumour has been investigated and considered as a promising treatment approach (19). More information regarding the structure, function, transport mechanism and homology modelling of LAT1 can be found in recently published studies and reviews (14,(20)(21)(22)(23)(24)(25)(26).…”

Development of Putative Isospecific Inhibitors for HDAC6 using Random Forest, QM-Polarized docking, Induced-fit docking, and Quantum mechanics

“…Molecular Mechanics Generalized Born Surface Area (MM-GBSA) evaluated the binding free energies (binding affinity) and minimized the docked protein-ligand complex. [41] Using VSGB 2.0 implicit solvation model and OPLS-2005. [42] The binding free energy was calculated using Eq.1…”

“…Briefly, the ligand and active site residue (side-chain and backbone) involved in the interactions are treated as the Quantum mechanics (QM) region while the other protein complex is treated as molecular mechanics (MM) region. The Qm calculation was done using Density functional theory (DFT) with Becke"s three-parameter exchange potential, Lee-Yang-Parr correlation functional (B3LYP) and basis set 631G ** level, [41] while MM region was treated using OPLS2005; minimization was done using Truncated Newton, maximum cycle:1000 with convergence criterion set to Energy Gradient. [41][47] All other parameters were left at default.…”

Virtual Screening and Elucidation of Putative Binding Mode for Small Molecule Antagonist of BCL2 BH4 Domain

“…Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) evaluated the binding free energies (binding affinity) and implemented geometric minimization of the docked proteinligand complex [18]. The binding free energy was calculated using VSGB 2.0 implicit solvation model and OPLS-2005 via Prime [19].…”

“…Where G complex , G protein, and G ligand represents the free binding energy of the protein-ligand complex, protein only, and ligand only respectively [18].…”