PMID- 31636293
OWN - NLM
STAT- MEDLINE
DCOM- 20201028
LR  - 20210110
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Oct 21
TI  - Rigorous sampling of docking poses unveils binding hypothesis for the halogenated 
      ligands of L-type Amino acid Transporter 1 (LAT1).
PG  - 15061
LID - 10.1038/s41598-019-51455-8 [doi]
LID - 15061
AB  - 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.
FAU - Singh, Natesh
AU  - Singh N
AUID- ORCID: 0000-0002-3897-1334
AD  - University of Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and 
      Molecules for living Systems, F-59000, Lille, France.
FAU - Villoutreix, Bruno O
AU  - Villoutreix BO
AUID- ORCID: 0000-0002-6456-7730
AD  - University of Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and 
      Molecules for living Systems, F-59000, Lille, France.
FAU - Ecker, Gerhard F
AU  - Ecker GF
AUID- ORCID: 0000-0003-4209-6883
AD  - Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 
      1090, Wien, Austria. gerhard.f.ecker@univie.ac.at.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191021
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Large Neutral Amino Acid-Transporter 1)
RN  - 0 (Ligands)
RN  - 47E5O17Y3R (Phenylalanine)
SB  - IM
MH  - Binding Sites
MH  - *Halogenation
MH  - Humans
MH  - Hydrogen Bonding
MH  - Large Neutral Amino Acid-Transporter 1/*chemistry/*metabolism
MH  - Ligands
MH  - *Molecular Docking Simulation
MH  - Phenylalanine/metabolism
MH  - Structural Homology, Protein
MH  - Structure-Activity Relationship
PMC - PMC6803698
COIS- The authors declare no competing interests.
EDAT- 2019/10/23 06:00
MHDA- 2020/10/29 06:00
PMCR- 2019/10/21
CRDT- 2019/10/23 06:00
PHST- 2019/06/27 00:00 [received]
PHST- 2019/09/24 00:00 [accepted]
PHST- 2019/10/23 06:00 [entrez]
PHST- 2019/10/23 06:00 [pubmed]
PHST- 2020/10/29 06:00 [medline]
PHST- 2019/10/21 00:00 [pmc-release]
AID - 10.1038/s41598-019-51455-8 [pii]
AID - 51455 [pii]
AID - 10.1038/s41598-019-51455-8 [doi]
PST - epublish
SO  - Sci Rep. 2019 Oct 21;9(1):15061. doi: 10.1038/s41598-019-51455-8.