Development of Covalent Ligand–Receptor Pairs to Study the Binding Properties of Nonpeptidic Neurotensin Receptor 1 Antagonists

The neurotensin receptor NTS1 has
been suggested to be of pharmaceutical relevance, as it was found
to exert modulatory effects on dopaminergic signal transduction and
to be involved in tumor progression. Rational drug design of NTS1
receptor ligands requires molecular insights into the binding behavior
of a particular lead compound. Although crystal structures of NTS1
have revealed the molecular determinants of peptide–agonist
interactions, the binding mode of small-molecule antagonists remains
largely unknown. Employing a disulfide-based tethering approach, we
developed covalently binding molecular probes. The ligands 1 and 2 are based on the pharmacophore of the nonpeptidic
NTS1 antagonist SR142948A, allowing the formation of a disulfide bond
to an engineered cysteine residue of NTS1. The position of the covalent
bond between Cys1272.65 and the ligand was used to predict
the binding mode of the covalent antagonist 1 and its
parent compound SR142948A by molecular dynamics simulations.