Dr. GPCR Podcast

Smells Like GPCR Spirit: Cracking Olfactory Codes with Alessandro Nicoli

1. The Accidental Path to Science

Alessandro Nicoli didn’t grow up knowing he’d be a scientist. Like many, his path to GPCR research wasn’t linear—it evolved through academic exploration and mentorship.

“I think I don’t have a linear trajectory… the beauty of seeing molecule design and reactions—thinking you can create molecules—was really exciting.” – Alessandro Nicoli

He studied pharmaceutical chemistry in Padua, where his fascination with molecular design first took shape. But it wasn’t until meeting an inspiring professor, Prof. Moro, that he truly saw how molecules could go beyond the bench and interact with biology in powerful ways.

2. The Moment Chemistry Met Biology

Nicoli’s turning point came when he realized that molecules weren’t static—they could act, bind, and modulate biological targets.

“It was not just a molecule—it was a partner that goes to interact with something else… a protein, DNA, RNA. That opened up a new world.” – Alessandro Nicoli

That early spark led him to discover the role of medicinal chemistry and, eventually, molecular modeling. For Nicoli, chemistry became more than reactions—it became a bridge to biological insight.

3. Falling for Computational Chemistry

The "second academic love" arrived during his master’s thesis, where Nicoli dove into computational chemistry.

“I got to know computational chemistry through a project on BCL2 proteins and drug discovery… I was in love with the topic.” – Alessandro Nicoli

Working on docking and NMR studies for cancer-related proteins, he discovered the power of simulation in revealing molecular interactions. That experience convinced him to pursue a PhD and deepen his computational skills—eventually leading him to GPCRs.

4. Finding the Right Mentor and Lab

A birthday email changed everything. Professor Moro forwarded a PhD opening from Prof. Antonella Di Pizio’s lab in Munich. It felt serendipitous—and it was.

“We had a super match… and after a month, I was already in Germany. I was her first PhD student.” – Alessandro Nicoli

Starting from scratch in a young lab wasn’t easy, but it created a unique bond between PI and student. Nicoli thrived in this setting—helping shape the lab and its direction, particularly in computational studies of olfactory GPCRs.

5. GPCRs, Receptors of Infinite Variety

When asked about his favorite GPCR, Nicoli refused to pick.

“Let’s embrace the challenge to study all of them… they’re unique in how they bind ligands, how selective they are.” – Alessandro Nicoli

He emphasized that olfactory receptors, while underexplored, present an incredible challenge. With hundreds of subtypes and very few known ligands, the structure–function relationships remain largely mysterious—and incredibly exciting for a computational chemist.

6. AlphaFold: A Turning Point in GPCR Research

When Nicoli began his PhD, AlphaFold hadn’t yet revolutionized the field. But once released, it changed everything.

“AlphaFold gave us a face to those proteins… now we have 400 models to start with.” – Alessandro Nicoli

He explained how AlphaFold’s predictions, surprisingly close to experimental structures, provided a powerful starting point for docking, dynamics, and ligand design—especially for receptors previously “invisible” to structural biology.

7. Modeling the Invisible: Olfactory Receptors

Nicoli’s work centers on predicting ligand binding and receptor behavior for olfactory GPCRs.

“The main challenge was: how do we get a face for these proteins when we don’t have ligands?” – Alessandro Nicoli

He shared a detailed case study of working on a specific odorant receptor (R5VK1), where they leveraged known active/inactive ligands to validate models through iterative refinement, molecular docking, and mutagenesis-guided optimization. The goal? Build predictive models to discover new ligands.

8. Why Molecular Dynamics Matters

For Nicoli, molecular dynamics is more than simulation—it’s how we watch biology move.

“You simulate over time… see how receptors move in physiological conditions, with water, membranes, ligands.” – Alessandro Nicoli

He emphasized that MD allows researchers to observe allosteric changes, mutation effects, and even ligand entry/exit paths, offering dynamic insights that static structures cannot. It’s a critical complement to experimental work.

9. From Researcher to Mentor: Growing Together

Outside his research, Nicoli mentors students, manages interns, and even lectures. Balancing this with a PhD isn't easy, but it’s deeply rewarding.

“You have people that rely on you… but you grow together, and that’s the most powerful thing.” – Alessandro Nicoli

He reflected on learning to delegate—how hard it was initially to hand over tasks—but how vital it is for team science. He now sees mentoring as a way to shape the next generation while evolving himself as a scientist.

10. Advice, Tools, and the Future of GPCR Research

Nicoli offered advice to wet-lab scientists curious about computational work:

• Start with passion.

• Learn Python.

• Explore online resources like “Talktorials.”

“We’re living in a golden era for computational chemistry… the tools are out there. You just need the motivation to explore.” – Alessandro Nicoli

As for what’s next? More structures, better tools, and deeper insights into the elegant, complex world of GPCRs. He sees a future where wet and dry labs converge, and where computational methods are fully integrated into GPCR drug discovery pipelines.

Summary made with AI

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Key Takeaway

Alessandro Nicoli’s journey is a compelling example of how computational chemistry can unlock new frontiers in GPCR research, especially in complex areas like olfactory receptors. By bridging structural prediction, molecular dynamics, and ligand discovery, his work not only deciphers biological mysteries but also inspires a new generation of scientists to think computationally.

Keyword Cloud

GPCR research community, Dr. GPCR ecosystem, GPCR online course, GPCR scientist network, GPCR drug discovery, GPCR training program, G protein-coupled receptors, GPCR podcast, GPCR webinar series, GPCR data platform

Summary created by AI

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About Alessandro Nicoli

Alessandro Nicoli is currently a PhD student in the Molecular Modeling group led by Prof. Dr. Antonella Di Pizio at the Leibniz Institute for Food Systems Biology at the Technical University of Munich (Germany).

He obtained an MSc degree in Chemistry and Pharmaceutical Technology from the University of Padua (Italy). His training and passion for computational chemistry started in 2019 during his time at the Molecular Modeling Section (MMS) under the supervision of Prof. Stefano Moro, where he worked on integrated Nuclear magnetic resonance (NMR) and computational modeling strategies to target the antiapoptotic BCL-2 protein family, key regulators of cell survival, using small molecules.

He then moved to Germany in 2019 to pursue his PhD. His research focuses on a group of 400 transmembrane proteins known as olfactory receptors, which mediate the sense of smell. Beyond the olfactory epithelium, these receptors are expressed in various tissues, where they play important but not yet fully understood roles in various physiological and pathological processes. Despite their relevance, they remain understudied due to the limited knowledge of their ligands and the lack of experimental structures. Alessandro PhD work aims to fill these gaps by leveraging computational structure-based tools and develop specific protocols to accelerate OR ligand discovery and improve our understanding of olfactory function at the molecular level.

Alessandro Nicoli on the web

• Leibniz Institute for Food Systems Biology at the Technical University of Munich

• Technical University of Munich

• Google Scholar

• Pubmed

• ORCID

• ResearchGate

• X

• Bluesky

• Github