Bitter taste in chicken – computational screening for bitter tastants · 2019-12-03 · and...
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Bitter taste in chicken – computational screening for bitter tastants Nitzan Sharabi, Antonella Di Pizio and Masha Y. Niv Institute of Biochemistry, Food Science and Nutrition, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot , Israel. Amirim Project 2015 Bi tter Taste role Bitter taste is known for its aversiveness in vertebrates, following the hypothesis that its role is to protect from ingesting certain bitter toxics . B itter taste receptors (Tas 2 Rs) have diverse crucial roles and are being expressed in tissues other than the palate, such as the respiratory system 1 and the gastric system 2 , where the bitter receptors signals trigger physiological actions such as the secretion of antimicrobial peptides in the nasal cavity 3 , or relaxing of the airway smooth muscles 1 . Complexity of bitter taste perception • There is no correlation between the number of Tas 2 R genes and the perception of bitter taste . • Receptors can have more than one binding pocket and more than one binding mechanism . • Many compounds binding to one receptor don’t have a similar chemical structure . • Some receptors are broadly tuned and some are narrowly tuned . Why chicken? Bitter taste perception in vertebrates relies on the Tas2R genes, ranging from only 3 in chicken to over 50 in frogs. Possessing a small repertoire of Tas2Rs making the chicken a suitable candidate for a model animal in the study of different aspects regarding bitter taste. Furthermore, the agricultural importance for finding bitter tastants in chicken feedstuff is great, since their nutrition may be improved due to lack of averssiveness. Introduction Materials and methods Results Figure 1. The process of building and validating LBP and shape models followed by virtual screening and in-vivo testing LBP models Quinine - APR Quinine - DHR Quinine - AHR Coumarin - ARR Name Features Fitness Shape similarity Ethylhydrocupreine APR 2.698 65% Cinchonine APR 2.433 58.1% Mefloquine APR 2.616 46.7% Cinchonidine DHR 2.534 55% Hydrocinchonine DHR 2.503 53% Table 1. Best hits for Tas2R1, Based on LBP’s with quinine as template Carisoprodol - ADH Carisoprodol - DDH Tas2R1 Tas2R2 Tas2R7 Conclusions References 1. Ligand based pharmacophore (LBP) modeling process Quinine - Cinchonine Quinine - Ethylhydrocupreine Quinine - Mefloquine Quinine – Hydrocinchonine-R Test Set 23 known agonists 23 known inactives Training Set Data Set Test Set Training Set Test Set Training Set Tas2R2 LBP models Best models with high selectivity Selected LBP models Quinine BitterDB DrugBank FoodDB Independent DB 2. Database preparation 3D Shape similarity virtual screening Virtual screening Computationally predicted hits Computationally predicted hits Combined hits for best possible results 3.Virtual screening Selected Hits Test experimentally Experimentally confirmed hits 4. In-Vivo testing Figure 3. Alignment of Best hits for Tas2R1 with quinine Figure 2. Selected LBP models for the three different receptors • Several molecules have been identified as promising candidates for agonism to Tas 2 R 1 . • Quinine analogs can be checked for antagonism, since they derive from the quinine agonist. • In - Vivo testing is ongoing, therefor comprehensive conclusions are still pending. • Future direction: In - Vitro experiments will be necessary in order to prove binding to a specific receptor. 1. Kathryn S. Robinett et al. Bitter Taste Receptor Function in Asthmatic and Nonasthmatic Human Airway Smooth Muscle Cells.Am J Respir Cell Mol Biol. 2014 Apr; 50 ( 4 ): 678 – 683 . 2. Sara Janssen and Inge Depoortere.Nutrient sensing in the gut: new roads to therapeutics. 2012 Elsevier Trends in Endocrinology and Metabolism xx ( 2012 ) 1 – 9 . 3. Robert J. Lee et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity.J Clin Invest. 2014 ; 124 ( 3 ): 1393 – 1405 .
Transcript of Bitter taste in chicken – computational screening for bitter tastants · 2019-12-03 · and...
Bitter taste in chicken –computational screening for bitter tastants
Nitzan Sharabi, Antonella Di Pizio and Masha Y. NivInstitute of Biochemistry, Food Science and Nutrition, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot , Israel. Amirim Project 2015
Bitter Taste roleBitter taste is known for its aversiveness invertebrates, following the hypothesis that its role is toprotect from ingesting certain bitter toxics. Bitter tastereceptors (Tas2Rs) have diverse crucial roles and arebeing expressed in tissues other than the palate, suchas the respiratory system1 and the gastric system2,where the bitter receptors signals trigger physiologicalactions such as the secretion of antimicrobial peptidesin the nasal cavity3, or relaxing of the airway smoothmuscles1.
Complexity of bitter taste perception• There is no correlation between the number of
Tas2R genes and the perception of bittertaste.
• Receptors can have more than one bindingpocket and more than one bindingmechanism.
• Many compounds binding to one receptordon’t have a similar chemical structure.
• Some receptors are broadly tuned and someare narrowly tuned.
Why chicken?Bitter taste perception in vertebrates relieson the Tas2R genes, ranging from only 3 inchicken to over 50 in frogs. Possessing asmall repertoire of Tas2Rs making thechicken a suitable candidate for a modelanimal in the study of different aspectsregarding bitter taste. Furthermore, theagricultural importance for finding bittertastants in chicken feedstuff is great, sincetheir nutrition may be improved due to lackof averssiveness.
Introduction
Materials and methods Results
Figure 1. The process of building and validating LBP and shape models followed by virtual screening and in-vivo testing
LBP models
Quinine - APR
Quinine - DHR
Quinine - AHR
Coumarin - ARR
Name Features Fitness Shape similarityEthylhydrocupreine APR 2.698 65%Cinchonine APR 2.433 58.1%Mefloquine APR 2.616 46.7%Cinchonidine DHR 2.534 55%Hydrocinchonine DHR 2.503 53%
Table 1. Best hits for Tas2R1, Based on LBP’s with quinine as template
Carisoprodol - ADH
Carisoprodol - DDH
Tas2R1Tas2R2Tas2R7
Conclusions References
1. Ligand based pharmacophore (LBP) modeling process
Quinine - Cinchonine Quinine - Ethylhydrocupreine Quinine - Mefloquine Quinine – Hydrocinchonine-R
Test Set
23 knownagonists
23 knowninactives
Training Set
Data Set
Test SetTraining Set
Test SetTraining Set
Tas2R2
LBP modelsBest models with high selectivity
Selected LBP models
Quinine
BitterDB
DrugBank
FoodDB
Independent DB
2. Database preparation
3D Shape similarity virtual screening
Virtual screening
Computationally predicted hits
Computationally predicted hits
Combined hits for best possible results
3.Virtual screening
Selected Hits Test experimentally Experimentally confirmed hits
4. In-Vivo testing
Figure 3. Alignment of Best hits for Tas2R1 with quinine
Figure 2. Selected LBP models for the three different receptors
• Several molecules have been identified as promising candidates for agonism to Tas2R1.
• Quinine analogs can be checked for antagonism, since they derive from the quinine agonist.
• In-Vivo testing is ongoing, therefor comprehensive conclusions are still pending.
• Future direction: In-Vitro experiments will be necessary in order to prove binding to a specific receptor.
1. Kathryn S. Robinett et al. Bitter Taste Receptor Function in Asthmatic and Nonasthmatic Human Airway Smooth Muscle Cells.Am J Respir Cell Mol Biol. 2014 Apr; 50(4): 678–683.
2. Sara Janssen and Inge Depoortere.Nutrient sensing in the gut: new roads to therapeutics. 2012 Elsevier Trends in Endocrinology and Metabolism xx (2012) 1–9.
3. Robert J. Lee et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity.J Clin Invest. 2014;124(3):1393–1405.
