title: Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues.
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 Tyr11residue 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 Lys11exhibited higher affinity toward the hNTS1-R212E mutant receptor, in which Arg212 was substituted by the negatively charged Glu residue.
authors.affiliation: Institut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université Montpellier, ENSCM , Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fanelli
authors.affiliation: Institut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université Montpellier, ENSCM , Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: Nicolas
authors.identifier: 0000-0002-3883-2852
authors.initials: N
authors.lastname: Floquet
authors.affiliation: Department of Pharmacology and Physiology, Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke , Sherbrooke J1H 5N4, Québec, Canada.
authors.forename: Élie
authors.identifier: 0000-0002-7473-7043
authors.initials: É
authors.lastname: Besserer-Offroy
authors.affiliation: Institut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université Montpellier, ENSCM , Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: Bartholomé
authors.initials: B
authors.lastname: Delort
authors.affiliation: Department of Pharmacology and Physiology, Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke , Sherbrooke J1H 5N4, Québec, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Vivancos
authors.affiliation: Department of Pharmacology and Physiology, Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke , Sherbrooke J1H 5N4, Québec, Canada.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Longpré
authors.affiliation: Institut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université Montpellier, ENSCM , Place Eugène Bataillon, 34095 Montpellier cedex 5, France.|Centre de Biochimie Structurale (CBS), UMR-5048, CNRS, Université de Montpellier, INSERM U1054 , 29 rue de Navacelles, 34090 Montpellier, France.
authors.forename: Pedro
authors.initials: P
authors.lastname: Renault
authors.affiliation: Institut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université Montpellier, ENSCM , Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: Jean
authors.identifier: 0000-0002-4551-4254
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Department of Pharmacology and Physiology, Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke , Sherbrooke J1H 5N4, Québec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.affiliation: Institut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université Montpellier, ENSCM , Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: Florine
authors.identifier: 0000-0001-5308-6416
authors.initials: F
authors.lastname: Cavelier
mesh_terms: D000595:Amino Acid Sequence; D015195:Drug Design; D056004:Molecular Dynamics Simulation; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000378:metabolism; D018028:Receptors, Neurotensin / Q000737:chemistry / Q000378:metabolism
chemical_list: D018028:Receptors, Neurotensin; D009496:Neurotensin