Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues.

TitreUse of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues.
Publication TypeJournal Article
Year of Publication2017
AuthorsFanelli R, Floquet N, Besserer-Offroy É, Delort B, Vivancos M, Longpre J-M, Renault P, Martinez J, Sarret P, Cavelier F
JournalJ Med Chem
Volume60
Issue8
Pagination3303-3313
Date Published2017 Apr 27
ISSN1520-4804
KeywordsAmino Acid Sequence, Drug Design, Molecular Dynamics Simulation, Neurotensin, Receptors, Neurotensin
Abstract

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 Tyr(11) residue of NT[8-13] with an acidic residue (Glu(179)) located in the ECL2 of hNTS2 or with a basic residue (Arg(212)) 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 Lys(11) exhibited higher affinity toward the hNTS1-R212E mutant receptor, in which Arg212 was substituted by the negatively charged Glu residue.

DOI10.1021/acs.jmedchem.6b01848
Alternate JournalJ. Med. Chem.
PubMed ID28368584