Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues

Neurotensin exerts
potent analgesia by acting at both NTS1 and
NTS2 receptors, whereas NTS1 activation also results in other physiological
effects such as hypotension and hypothermia. Here, we used molecular
modeling approach to design highly selective NTS2 ligands by investigating
the docking of novel NT­[8-13] compounds at both NTS1 and NTS2 sites.
Molecular dynamics simulations revealed an interaction of the Tyr11 residue of NT­[8-13] with an acidic residue (Glu179) located in the ECL2 of hNTS2 or with a basic residue (Arg212) at the same position in hNTS1. The importance of the residue at
position 11 for NTS1/NTS2 selectivity was further demonstrated by
the design of new NT analogues bearing basic (Lys, Orn) or acid (Asp
or Glu) function. As predicted by the molecular dynamics simulations,
binding of NT­[8-13] analogues harboring a Lys11 exhibited
higher affinity toward the hNTS1-R212E mutant receptor, in which Arg212
was substituted by the negatively charged Glu residue.