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J Med Chem. 2017 Apr 27;60(8):3303-3313. doi: 10.1021/acs.jmedchem.6b01848. Epub 2017 Apr 10.

Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues.

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Institut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université Montpellier, ENSCM , Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
Department of Pharmacology and Physiology, Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke , Sherbrooke J1H 5N4, Québec, Canada.
Centre de Biochimie Structurale (CBS), UMR-5048, CNRS, Université de Montpellier, INSERM U1054 , 29 rue de Navacelles, 34090 Montpellier, France.


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.

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