Grafted hyaluronic acid N-acetyl-l-methionine for targeting of LAT1 receptor: In-silico, synthesis and microscale thermophoresis studies.

Neutral amino acids can be delivered into cells through the l-type amino acid transporter-1 (LAT1), which is a sodium independent transporter. The LAT1 protein is expressed in different tissues, including kidney, blood brain barrier and intestinal wall hence LAT1 can be used as a target in diseases associated with its overexpression. In-silico interactions between different ligands, including methionine (Met), N-acetyl-l-methionine (AcMet), hyaluronic acid (HA), grafted hyaluronic-acid l-methionine (HA-ADH-Met) and a novel grafted hyaluronic acid-N-acetyl-l-methionine (HA-ADH-AcMet), which are at the active site of the LAT1 transporter, were studied and the binding energies calculated. The HA-ADH-AcMet complex demonstrated binding energy and solvation energy of -74.84 and 81.46 kcal/mol, respectively, thus validating its potential to be synthesized. The structural conformation of the HA-ADH-AcMet was confirmed using 1H NMR, FTIR, DSC and PXRD. Microscale thermophoresis was employed to study the binding affinity between the different ligands and LAT1. The binding affinity was expressed in terms of a dissociation constant (Kd), where that of HA-ADH-AcMet was found to be 408 nM which was considered the strongest among the different ligands tested. HA-ADH-AcMet can be used as a targeting moiety for development of medicines to treat different diseases and processes that express LAT1 protein.