David Gloriam: Orphan Receptors, GPCRDB, and the Data Revolution in GPCR Pharmacology

GPCRs represent the largest and most pharmacologically important family of membrane receptors, yet a significant portion remain orphans - proteins whose endogenous ligands and physiological roles are still unknown. This conversation explores the intersection of computational biology, cheminformatics, and structural pharmacology through the work of David Gloriam, whose career spans the identification of 26 novel human GPCRs from genome sequence data to the development of GPCRDB, a community resource used by more than 4,400 researchers monthly.

Gloriam's research addresses a central challenge in the field: how to move from a bare protein sequence to a pharmacologically characterized receptor with identified ligands, a determined structure, and a plausible role in physiology. The conversation covers the de-orphanization of GPR139 and GPR55, the unresolved promise of biased agonism as a strategy for safer drug development, and the concept of data-accelerated receptor evolution as a framework for engineering receptor-ligand interactions at the residue level.

For Gloriam, this work began with a grandmother's cancer diagnosis and an early determination to develop drugs - a goal that led him through the human genome and into a decades-long pursuit of receptors whose functions remain to be written.

ABOUT THE GUEST

David Gloriam is a professor at the University of Copenhagen's Department of Drug Design and Pharmacology, where he leads a multidisciplinary research group working across data science, computational drug design, pharmacology, and structural biology. His primary research focus is orphan GPCR biology, with particular emphasis on identifying endogenous ligands and physiological roles for receptors discovered during the human genome sequencing era.

He maintains and develops GPCRDB, a continuously updated database and tool platform that integrates structural, functional, and ligand data for the entire GPCR superfamily. His group contributed to the de-orphanization of GPR139 and GPR55, including the identification of sub-nanomolar peptide ligand candidates, and has published widely on computational approaches to GPCR drug discovery and receptor classification.

SCIENTIFIC THEMES OF THE CONVERSATION

1. Orphan GPCR biology - the challenge of connecting a protein sequence to a physiological function
   

2. GPCRDB as community infrastructure for integrating and accelerating GPCR research
   

3. The interdisciplinary de-orphanization pipeline: from bioinformatics to pharmacology to structure
   

4. The data interpretation bottleneck - how the field's rate-limiting step has fundamentally shifted
   

5. Biased agonism: from theoretical framework to the challenge of pathway-specific drug design
   

6. Data-accelerated receptor evolution: engineering GPCR function at the single residue level

KEY INSIGHTS FROM THE CONVERSATION

The Human Genome as a Discovery Platform

When Gloriam joined a bioinformatics group during his master's studies, the first human genome sequence had just become available. Working within that resource, his group identified 26 previously unknown GPCRs in the span of a few years - a pace of discovery that would have been impossible through classical biochemical approaches. The experience established his conviction that computational analysis could function as a genuine primary discovery tool, not merely as support for bench science.

De-Orphanization Is a Full-Discipline Effort

The process of characterizing an orphan receptor from protein sequence to identified ligand to determined structure cannot be completed within a single lab or a single methodology. Gloriam described the journey of GPR139 as spanning sequence-based phylogeny, database mining for tissue expression, virtual screening, pharmacological assay development, machine learning-guided ligand identification, and finally structural collaboration with external groups. The full arc took more than a decade and required sustained coordination across disciplines that rarely share a lab bench.

Taking Over GPCRDB Without a Safety Net

When the original GPCRDB team approached retirement, Gloriam chose to carry the resource forward despite holding no tenure and working under a two-year contract. He described it as one of the major single decisions of his career - a bet that the community would respond and the opportunity would justify the risk. The response exceeded his expectations: within years, researchers he had never met were greeting him at conferences by name because of the database.

The Bottleneck Has Flipped

For most of the history of pharmacological research, generating reliable data was the rate-limiting step. Gloriam argued that this has fundamentally changed: the volume and diversity of available data now far outpaces the field's capacity to analyze and interpret it. This shift places data scientists and computational biologists in a newly central role - not as support for experimentalists, but as the primary constraint to overcome in advancing receptor biology.

Biased Agonism Still Needs Its Proof of Concept

A drug designed around biased agonism principles received regulatory approval, but its actual functional selectivity has since been questioned - with some researchers arguing it may be a partial agonist rather than a genuinely biased compound. Gloriam identified this ambiguity as symptomatic of a deeper challenge: the field has not yet fully characterized which signaling pathways produce therapeutic benefit and which produce side effects across the GPCR targets most relevant to disease. Until that pathway-level map is built, designing genuinely biased drugs remains a hypothesis in search of its first clean demonstration.

Leadership Is a Learnable Skill - If You Seek the Training

Gloriam took formal research leadership training before his group was large enough to require it - acting on advice from mentors who recognized that funding panels wanted evidence of leadership readiness alongside scientific merit. He described coaching sessions, national leadership courses, and the deliberate selection of mentors who had recently navigated the specific challenges he was facing. The result was a structured group management model built around four specialized subgroups, each with a senior researcher as daily supervisor - a design that reduced bottlenecks and allowed the science to scale beyond what one group leader could hold.

Open Science as the Next Infrastructure Problem

Gloriam articulated a vision for GPCRDB as more than a data repository - a shared scientific workspace where researchers could surface big unsolved problems, correspond across institutions, design experiments collectively, and deposit results in a structured format accessible to the entire community. He described the complete characterization of biased signaling pathways across all GPCRs as one such challenge: too large for any single group, and structurally dependent on coordinated community effort that currently has no home.

EPISODE TIMELINE

Timestamps are AI-generated estimates based on the transcript and may not align exactly with the final edited episode. Verify against the published audio before use.

• 00:00 Welcome and introduction of David Gloriam

• 02:23 Career origins - from childhood medicine ambitions to pharmaceutical sciences and bioinformatics

• 05:34 The human genome treasure hunt - discovering 26 new GPCRs from sequence data

• 11:55 Orphan GPCRs - years spent chasing receptors with no known function or ligand

• 13:31 De-orphanizing GPR55 and GPR139 - the full pipeline from sequence to structure

• 17:21 GPCRDB - origin story, the career-defining decision to take it over, and its growth

• 23:21 Two frontiers: residue-level receptor function and the unresolved challenge of biased agonism

• 30:29 Managing a multidisciplinary group of 15 - subgroups, leadership training, and delegation

• 40:41 What excites Gloriam today - open science models and the long-term vision for GPCRDB

• 50:01 Career-defining moments, work-life balance, and advice for junior scientists

SELECTED QUOTES

About this episode

David Gloriam is a Professor in Computational Receptor Biology at the University of Copenhagen where he leads a research cluster for GPCR function and drug discovery and a Pharmaceutical Data Science unit. His group runs the GPCRdb database where ~4,000 researchers each month retrieve reference data and access online tools for analysis, visualization, and experiment design.

David obtained his Ph.D. from Uppsala University in Sweden where he worked on the bioinformatic identification of 24 novel human G protein-coupled receptors. He later identified physiological hormones of such under characterized ‘orphan’ receptors and functional probes for a range of receptors. He completed two postdocs in the UK at the EMBL-European Bioinformatics Institute and GlaxoSmithKline.

In 2018 he joined the University of Copenhagen, where he has received an ERC Starting Grant, Lundbeck Foundation Fellowship, and Novo Nordisk Foundation Ascending Investigator awards.

Dr. Gloriam is a corresponding member of the Nomenclature Committee of the International Union of Pharmacology (IUPHAR). He is one of the coordinators of recommendations to describe ligand bias towards signaling probes and safer drugs. His group recently developed an online resource of biased ligands and pathway effects to advance the biased signaling field.

Join me a learn more about David’s work, his career trajectory, and GPCRdb.

Dr. David E. Gloriam on the web

• LinkedIn

• ResearchGate

• Twitter

• Google Scholar

• Computation Receptor Biology- Gloriam Group

• GPCRdb

• Dr. GPCR Ecosystem