Discovery of a Novel Chemo-Type for TAAR1 Agonism via Molecular Modeling

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Discovery of a Novel Chemo-Type for TAAR1 Agonism via Molecular Modeling. / Grossi, Giancarlo; Scarano, Naomi; Musumeci, Francesca; Tonelli, Michele; Kanov, Evgeny; Carbone, Anna; Fossa, Paola; Gainetdinov, Raul R.; Cichero, Elena; Schenone, Silvia.

In: Molecules, Vol. 29, No. 8, 1739, 11.04.2024.

Research output: Contribution to journal › Article › peer-review

Author

Grossi, Giancarlo ; Scarano, Naomi ; Musumeci, Francesca ; Tonelli, Michele ; Kanov, Evgeny ; Carbone, Anna ; Fossa, Paola ; Gainetdinov, Raul R. ; Cichero, Elena ; Schenone, Silvia. / Discovery of a Novel Chemo-Type for TAAR1 Agonism via Molecular Modeling. In: Molecules. 2024 ; Vol. 29, No. 8.

BibTeX

@article{03e1d0bb956f4752b369a13385a01cad,

title = "Discovery of a Novel Chemo-Type for TAAR1 Agonism via Molecular Modeling",

abstract = "The search for novel effective TAAR1 ligands continues to draw great attention due to the wide range of pharmacological applications related to TAAR1 targeting. Herein, molecular docking studies of known TAAR1 ligands, characterized by an oxazoline core, have been performed in order to identify novel promising chemo-types for the discovery of more active TAAR1 agonists. In particular, the oxazoline-based compound S18616 has been taken as a reference compound for the computational study, leading to the development of quite flat and conformationally locked ligands. The choice of a {"}Y-shape{"} conformation was suggested for the design of TAAR1 ligands, interacting with the protein cavity delimited by ASP103 and aromatic residues such as PHE186, PHE195, PHE268, and PHE267. The obtained results allowed us to preliminary in silico screen an in-house series of pyrimidinone-benzimidazoles ( 1a- 10a) as a novel scaffold to target TAAR1. Combined ligand-based (LBCM) and structure based (SBCM) computational methods suggested the biological evaluation of compounds 1a- 10a, leading to the identification of derivatives 1a- 3a (hTAAR1 EC 50 = 526.3-657.4 nM) as promising novel TAAR1 agonists. ",

keywords = "Benzimidazoles/chemistry, Binding Sites, Drug Discovery, Humans, Ligands, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Oxazoles/chemistry, Protein Binding, Receptors, G-Protein-Coupled/agonists, Structure-Activity Relationship",

author = "Giancarlo Grossi and Naomi Scarano and Francesca Musumeci and Michele Tonelli and Evgeny Kanov and Anna Carbone and Paola Fossa and Gainetdinov, {Raul R.} and Elena Cichero and Silvia Schenone",

year = "2024",

month = apr,

day = "11",

doi = "10.3390/molecules29081739",

language = "English",

volume = "29",

journal = "Molecules",

issn = "1420-3049",

publisher = "MDPI AG",

number = "8",

}

RIS

TY - JOUR

T1 - Discovery of a Novel Chemo-Type for TAAR1 Agonism via Molecular Modeling

AU - Grossi, Giancarlo

AU - Scarano, Naomi

AU - Musumeci, Francesca

AU - Tonelli, Michele

AU - Kanov, Evgeny

AU - Carbone, Anna

AU - Fossa, Paola

AU - Gainetdinov, Raul R.

AU - Cichero, Elena

AU - Schenone, Silvia

PY - 2024/4/11

Y1 - 2024/4/11

N2 - The search for novel effective TAAR1 ligands continues to draw great attention due to the wide range of pharmacological applications related to TAAR1 targeting. Herein, molecular docking studies of known TAAR1 ligands, characterized by an oxazoline core, have been performed in order to identify novel promising chemo-types for the discovery of more active TAAR1 agonists. In particular, the oxazoline-based compound S18616 has been taken as a reference compound for the computational study, leading to the development of quite flat and conformationally locked ligands. The choice of a "Y-shape" conformation was suggested for the design of TAAR1 ligands, interacting with the protein cavity delimited by ASP103 and aromatic residues such as PHE186, PHE195, PHE268, and PHE267. The obtained results allowed us to preliminary in silico screen an in-house series of pyrimidinone-benzimidazoles ( 1a- 10a) as a novel scaffold to target TAAR1. Combined ligand-based (LBCM) and structure based (SBCM) computational methods suggested the biological evaluation of compounds 1a- 10a, leading to the identification of derivatives 1a- 3a (hTAAR1 EC 50 = 526.3-657.4 nM) as promising novel TAAR1 agonists.

AB - The search for novel effective TAAR1 ligands continues to draw great attention due to the wide range of pharmacological applications related to TAAR1 targeting. Herein, molecular docking studies of known TAAR1 ligands, characterized by an oxazoline core, have been performed in order to identify novel promising chemo-types for the discovery of more active TAAR1 agonists. In particular, the oxazoline-based compound S18616 has been taken as a reference compound for the computational study, leading to the development of quite flat and conformationally locked ligands. The choice of a "Y-shape" conformation was suggested for the design of TAAR1 ligands, interacting with the protein cavity delimited by ASP103 and aromatic residues such as PHE186, PHE195, PHE268, and PHE267. The obtained results allowed us to preliminary in silico screen an in-house series of pyrimidinone-benzimidazoles ( 1a- 10a) as a novel scaffold to target TAAR1. Combined ligand-based (LBCM) and structure based (SBCM) computational methods suggested the biological evaluation of compounds 1a- 10a, leading to the identification of derivatives 1a- 3a (hTAAR1 EC 50 = 526.3-657.4 nM) as promising novel TAAR1 agonists.

KW - Benzimidazoles/chemistry

KW - Binding Sites

KW - Drug Discovery

KW - Humans

KW - Ligands

KW - Models, Molecular

KW - Molecular Docking Simulation

KW - Molecular Structure

KW - Oxazoles/chemistry

KW - Protein Binding

KW - Receptors, G-Protein-Coupled/agonists

KW - Structure-Activity Relationship

UR - https://www.mendeley.com/catalogue/75ef6fce-a9bd-3dcc-938c-88f520c0e6ec/

U2 - 10.3390/molecules29081739

DO - 10.3390/molecules29081739

M3 - Article

C2 - 38675561

VL - 29

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 8

M1 - 1739

ER -

ID: 119051915