10:00 - 12:00
Sat-S11
Goethe Hall
Chair/s:
Antonella Di Pizio, Sébastien Fiorucci
Computational approaches are widely used to get insights into the chemistry and biology of chemosensation. The ECRO Special Interest Group Computational Chemosensation aims to gather researchers working in computational chemosensation, to facilitate their interaction and advance computational techniques for chemical senses, but also promote the potential of computational works to promote collaborations with experimentalists. The proposed symposium is the first initiative of the group and aims to highlight computationally guided advancements in chemosensation, ranging from machine learning based predictors, to the use of computer-aided drug design tools for ligand discovery, to the multiscale simulations of chemosensory receptors, to network analyses of proteins and signaling events. Works on both taste and smell will be presented in the symposium. We expect that bringing together computational researchers from different fields will provide stimulating and fruitful discussions about future perspectives. Moreover, during the symposium, the ECRO special interest group will be introduced to the audience.
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The antagonists' challenge: finding new molecules for bitter taste receptor inhibition
Sat-S11-005
Presented by: Fabrizio Fierro
Fabrizio Fierro 1, Lior Peri 1, Lukas Waterloo 2, Alina Tabor-Schkade 2, Tamir Dingjan 3, Eitan Margulis 1, Herald Hübner 2, Peter Gmeiner 2, Masha Niv 1
1 Hebrew University of Jerusalem, Faculty of Agriculture, Rehovot, Israel, 2 Friedrich-Alexander-Universität Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Erlangen, Germany, 3 Weizmann Institute of Science, Department of Biomolecular Sciences, Rehovot, Israel
Over 1000 agonists are known to activate the 25 members of the human bitter taste receptor family, with bitter taste receptor T2R14 being the most promiscuous (1) . Despite its 152 known agonists, only 3 antagonists are known, all sharing the same scaffold. Inhibiting T2Rs may help mask the undesired bitter taste of food and drugs. Due to the extra-oral expression of taste receptors, modulation of the receptor is interesting for studying extraoral roles and potential pharmaceutical applications. No experimental structure is available for any of the T2Rs, and the sequence identity with other GPCRs is very low, strongly affecting the potential of structure-based drug discovery methodologies.
To address this challenge, we applied a mixed computational/experimental iterative methodology that allows for the identification of new ligands while refining the receptor structure at every step of the cycle. The initial set of ligands was employed to generate thousands of conformations of the T2R14 homology model through induced-fit docking, and, subsequently, to evaluate their performances in discriminating active ligands from decoys. Virtual screening of a multi-million library of compounds was performed using docking to the top-performing receptor conformation. Mixed structure/ligand-based approaches were also applied and potential candidates were experimentally tested. Compounds discovered in each iteration were combined with new data from cell-based screening clinical drugs and newly synthesized molecules. Overall, the number of antagonists was tripled, and their selectivity towards T2R14 was suggested by the BitterMatch computational tool (2). Over 200 new agonists have been discovered, and optimized 3D models of T2R14 were obtained.
The results stress the importance of integration of experimental and computational approaches and provide new chemical probes for inhibiting T2R14.

1. A. Di Pizio et al. Cell Mol Life Sci (2020)
2. E. Margulis et al. bioRxiv (2022)
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