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Dr. Antonella Di Pizio: Computational Pharmacology of Taste and Olfactory Receptors

Chemosensory receptors — bitter taste receptors (TAS2Rs), odorant receptors, and trace amine-associated receptors (TAARs) — sit among the most structurally underserved families of class A GPCRs. No crystal structures exist for most of them, sequence identity within the TAS2R family hovers between 15% and 19%, and several members are effectively orphans with only a handful of known ligands.

Yet these receptors appear to govern far more than flavor and smell. Bitter taste receptors have been identified in the heart and intestine, olfactory receptors in the brain, and the TAARs sit at the interface between neurotransmission and chemoreception — with clinical interest emerging in schizophrenia, neurodegeneration, depression, and anxiety.

In this conversation, Dr. Antonella Di Pizio — who leads the computational pharmacology group at the Leibniz Institute for Food Systems Biology at the Technical University of Munich — describes how she uses homology modeling, docking, molecular dynamics, and iterative mutagenesis to probe these systems. For her, the work isn't abstract: she spent five months staring at empty protein crystals during her PhD, and learned that the distance between giving up and seeing a ligand inside a binding pocket can be measured in weeks.

About the Guest

Dr. Antonella Di Pizio is an independent research group leader in computational pharmacology at the Leibniz Institute for Food Systems Biology at the Technical University of Munich, where she was the first group leader appointed to the institute's newly-formed in-silico department. Trained as a medicinal chemist at the University of Chieti in Italy, she completed her PhD in computational medicinal chemistry before spending a formative period in Gerhard Klebe's structural biology lab in Marburg. Her postdoctoral training in Masha Niv's lab in Israel marked her first work on GPCRs, specifically the bitter taste receptors (TAS2Rs). Her group now studies taste receptors, odorant receptors, and trace amine-associated receptors using a combination of homology modeling, docking, molecular dynamics, and virtual screening — tightly integrated with experimental mutagenesis and functional assays through collaborations.

Scientific Themes of the Conversation

Chemosensory receptors as a frontier for GPCR drug discovery
Trace amine-associated receptors (TAARs) and their neurological relevance
Promiscuity and selectivity within the bitter taste receptor family
Iterative integration of computational modeling with experimental mutagenesis
Ectopic expression of taste and odorant receptors beyond their namesake tissues
Persistence, career building, and what it means to lead a first-generation computational group

Key Insights from the Conversation

The first in-silico group inside a food biology institute. When Dr. Di Pizio arrived in October 2018, she founded the first computational group in an institute whose original identity had been food chemistry. Her job description — computational pharmacology — was itself an attempt to name a new interface between food chemistry and receptor pharmacology.

TAARs look more classical than most chemosensory GPCRs — and that matters for modeling. Unlike bitter taste receptors, which share only 5–10% sequence identity with available structural templates, the TAARs share roughly 30% identity with the β2-adrenergic receptor. That proximity transforms what's computationally tractable, making homology modeling genuinely predictive rather than speculative.

TAAR5 is effectively orphan — and may be a new kind of antidepressant target. With only about five known agonists, TAAR5 sits in a pharmacological twilight. Yet knockout mice show anti-anxiety, anti-depressant phenotypes, and expression of the receptor in the brain alters serotonin levels. An antagonist of TAAR5 could, in principle, seed a new class of psychiatric therapy.

Bitter is not only about taste. TAS2Rs have been identified in the heart and intestine; olfactory receptors in the brain. What they do there remains largely unknown. But evidence is accumulating that bitter taste receptors participate in innate immunity, recognizing bacterial secretions that happen to register as bitter on the tongue.

A bitter receptor is already in phase 2 clinical trials. Isohumulones — the hop-derived bitter compounds that give beer its characteristic flavor — have shown anti-diabetic activity in clinical development. The receptor responsible, TAS2R1, is expressed in the intestine. The drug candidate was never designed as a bitter receptor ligand; the receptor was identified post-hoc.

Computational pharmacology is not a downstream silo. Dr. Di Pizio's workflow is deliberately iterative: build the model, predict binding-site residues, send them out for mutagenesis, fold the experimental results back into the model, rebuild. Collaborators are not recipients of finished predictions — they are partners embedded in the modeling loop itself.

Five months of empty crystals, then a ligand. During her PhD, Dr. Di Pizio spent five months crystallizing carbonic anhydrase 2 with small molecules and seeing only empty proteins at the synchrotron. Two weeks before her internship ended, after changing every parameter she could think of, she finally saw her ligand inside the binding pocket. She describes it as the happiest moment of her scientific life — and, for a computational chemist, a lasting lesson in what sits behind every coordinate file.

Episode Timeline

Timestamps were generated using AI for readability.

00:00 Introduction
01:46 Computational pharmacology inside a food systems institute
03:13 From medicinal chemistry to bitter taste receptors
05:44 Trace amine-associated receptors on the edge of neuroscience
12:34 Anosmia and viruses of the olfactory system
19:03 Inside a computational workflow for orphan receptors
29:14 Bitter receptors in the heart and gut
30:43 A bitter receptor in phase 2 clinical trials
43:40 Five months of empty crystals
55:56 Rebuilding a research group during lockdown

Selected Quotes

"We don't have any crystal structures. So the research is more food-oriented and food-chemistry-oriented — this is why we have knowledge about compounds, but we don't have a lot of knowledge about quantitative structure-activity relations based on the structure of the receptor."

"For five months, my protein was always empty at the X-ray. And two weeks before I had to leave, I finally saw my ligand inside the pocket. For me, I think that was my happiest moment in my life."

"You share your research goal with your collaborators. They are more partners than collaborators."

"Think of being an investor of yourself. Read, study, do the most as you can to learn as much as you can — not only scientifically, but also networking. Be passionate on exactly the field that you work on, because this will be extremely useful later."

About this episode

In this episode of the Dr. GPCR podcast, we meet with Dr. Antonella Di Pizio, an independent research group leader at the Leibniz Institute for Food Systems Biology at the Technical University of Munich. Antonella trained as a medicinal chemist in Italy, followed by a Ph.D. in computational medicinal chemistry, during which she developed a taste for structural biology. Antonella then moved to Israel, where she first started working on bitter taste GPCRs in Dr. Masha Niv's lab. Today, Antonella has expanded her research to olfactory GPCRs and trace amine receptors. Join us to learn more about chemosensory GPCRs and how computational pharmacology can help better understand their function.

Dr. Antonella Di Pizio on the web