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5. Smell and taste changes are early indicators of the COVID-19 pandemic and political decision effectiveness

Author

Pierron, Denis, Pereda-Loth, Veronica, Mantel, Marylou, Moranges, Maëlle, Bignon, Emmanuelle, Alva, Omar, Kabous, Julie, Heiske, Margit, Pacalon, Jody, David, Renaud, Dinnella, Caterina, Spinelli, Sara, Monteleone, Erminio, Farruggia, Michael C., Cooper, Keiland W., Sell, Elizabeth A., Thomas-Danguin, Thierry, Bakke, Alyssa J., Parma, Valentina, Hayes, John E., Letellier, Thierry, Ferdenzi, Camille, Golebiowski, Jérôme, and Bensafi, Moustafa

Published
2020
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6. Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor

Author

Panel, Nicolas, Vo, Duc Duy, Kahlous, Nour Aldin, Huebner, Harald, Tiedt, Stephanie, Matricon, Pierre, Pacalon, Jody, Fleetwood, Oliver, Kampen, Stefanie, Luttens, Andreas, Delemotte, Lucie, Kihlberg, Jan, Gmeiner, Peter, Carlsson, Jens, Panel, Nicolas, Vo, Duc Duy, Kahlous, Nour Aldin, Huebner, Harald, Tiedt, Stephanie, Matricon, Pierre, Pacalon, Jody, Fleetwood, Oliver, Kampen, Stefanie, Luttens, Andreas, Delemotte, Lucie, Kihlberg, Jan, Gmeiner, Peter, and Carlsson, Jens

Abstract

G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high-resolution receptor structures are available. We performed molecular dynamics simulations of the beta(2) adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds. Previously identified ligands were successfully classified into groups with comparable efficacy profiles based on the calculated shift in ligand affinity upon activation. A series of ligands were then predicted and synthesized, leading to the discovery of partial agonists with nanomolar potencies and novel scaffolds. Our results demonstrate that free energy simulations enable design of ligand efficacy and the same approach can be applied to other GPCR drug targets., QC 20240222

Published
2023

9. Design of Drug Efficacy Guided by Free Energy Simulations of the β2‐Adrenoceptor

Author

Panel, Nicolas, primary, Vo, Duc Duy, additional, Kahlous, Nour Aldin, additional, Hübner, Harald, additional, Tiedt, Stephanie, additional, Matricon, Pierre, additional, Pacalon, Jody, additional, Fleetwood, Oliver, additional, Kampen, Stefanie, additional, Luttens, Andreas, additional, Delemotte, Lucie, additional, Kihlberg, Jan, additional, Gmeiner, Peter, additional, and Carlsson, Jens, additional

Published
2023
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11. Trace amine associated receptors (TAARs) response to amines are largely affected by sequences variants

Author

Pacalon, Jody, Belloir, Christine, Fiorucci, Sébastien, Briand, Loïc, Topin, Jérémie, and Julien, Sabine

Subjects
[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract

The Trace Amine Associated Receptors (TAARs) are a family of chemosensory receptors that recognize volatile amines. These receptors are few in number and highly conserved, compared to regular olfactory receptors. Polymorphisms in the TAAR family can have a drastic impact on our perception of amine compounds. Our study combine numerical simulations with in vitro experiments to reveal the activation mechanisms of the human TAAR5 receptor. The study focused on the hTAAR5-S95P polymorphism, which is found at high frequency in Nordic countries. This mutation affects the perception of trimethylamine (TMA), making individuals less able to perceive the smell of rotten fish caused by this molecule. The study's 3D model captures the inability of the hTAAR5-S95P variant to be activated by TMA in vitro, as well as the activation of the receptor by different agonists. Long-scale molecular dynamics simulations were used to study the system bound to ligands with different efficacies, providing insight into the features of a prototypical active state of G protein-coupled receptors. The study has identified two specific features of the TAAR family that are responsible for the altered perception of TMA in individuals with this polymorphism.

Published
2022

12. Design of Drug Efficacy Guided by Free Energy Simulations of the β2‐Adrenoceptor.

Author

Panel, Nicolas, Vo, Duc Duy, Kahlous, Nour Aldin, Hübner, Harald, Tiedt, Stephanie, Matricon, Pierre, Pacalon, Jody, Fleetwood, Oliver, Kampen, Stefanie, Luttens, Andreas, Delemotte, Lucie, Kihlberg, Jan, Gmeiner, Peter, and Carlsson, Jens

Subjects
DRUG design, DRUG efficacy, ADRENERGIC receptors, MOLECULAR dynamics, DRUG target, LIGAND binding (Biochemistry)
Abstract

G‐protein‐coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high‐resolution receptor structures are available. We performed molecular dynamics simulations of the β2 adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds. Previously identified ligands were successfully classified into groups with comparable efficacy profiles based on the calculated shift in ligand affinity upon activation. A series of ligands were then predicted and synthesized, leading to the discovery of partial agonists with nanomolar potencies and novel scaffolds. Our results demonstrate that free energy simulations enable design of ligand efficacy and the same approach can be applied to other GPCR drug targets. [ABSTRACT FROM AUTHOR]

Published
2023
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13. Large-Scale G Protein-Coupled Olfactory Receptor–Ligand Pairing

Author

Cong, Xiaojing, primary, Ren, Wenwen, additional, Pacalon, Jody, additional, Xu, Rui, additional, Xu, Lun, additional, Li, Xuewen, additional, de March, Claire A., additional, Matsunami, Hiroaki, additional, Yu, Hongmeng, additional, Yu, Yiqun, additional, and Golebiowski, Jérôme, additional

Published
2022
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15. Self-reported smell and taste changes are early indicators of the COVID- 1 19 pandemic and of the effectiveness of political decisions 2 3 4

Author

Pierron, Denis, Pereda-Loth, Veronica, Mantel, Marylou, Moranges, Maëlle, Bignon, Emmanuelle, Alva, Omar, Kabous, Julie, Heiske, Margit, Pacalon, Jody, David, Renaud, Dinnella, Caterina, Spinelli, Sara, Monteleone, Erminio, Farruggia, Michael, Cooper, Keiland, Hayes, John, Sell, Elizabeth, Thomas-Danguin, Thierry, Bakke, Alyssa, Parma, Valentina, Hayes, E, Letellier, Thierry, Ferdenzi, Camille, Golebiowski, Jérôme, Bensafi, Moustafa, Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Mémoire de Ressources et de Recherche [Nice] (CMRR Nice), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Yale University [New Haven], University of California [Irvine] (UCI), University of California, University of Pennsylvania [Philadelphia], Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Pennsylvania State University (Penn State), Penn State System, Temple University, Daegu Gyeongbuk Institute of Science and Technology, and Projet Global Consortium for Chemosensory Research (GCCR).

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract

In response to the COVID-19, many governments have taken unprecedented measures in peacetime, to avoid an overflow of intensive care units and critical care resuscitation units (CCRUs). Due to the heavy societal and economic impact of measure such as the lockdown1, accurate means to characterize the spread of the disease would be extremely helpful for the reopening strategies. Concurrently, smell and taste changes have been identified as among the most specific symptoms of COVID-192,3. Here, we show that self-reports of smell/taste changes are more closely associated with hospital overload and are much earlier than the current governmental indicators. We also show a decrease of new onset as early as 5 days after the lockdown enforcement, which is consistent with a rapid effect of the lockdown on the pandemic. Cross-country comparisons show countries with the most stringent lockdown measures (France and Italy) present a faster decline in new reports of the onset of smell/taste changes after the lockdown than a country with less stringent measures (United Kingdom). Public health decision makers could thus monitor self-reported changes in the ability to smell or taste i/as an early and specific indicator of the COVID-19 pandemic, and ii/to evaluate the success of reopening strategies.

Published
2020

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