Category Archives: Drug Discovery

OAS-nano: New Repertoire Database Just Dropped

Those familiar with the immunoinformatics work of our group will know of our Observed Antibody Space (OAS) and Observed T-cell Receptor Space (OTS) databases, which compile and consistently process V(D)J transcriptomics datasets from across a range of studies on natural immune repertoires. These have provided a central community resource of training data for adaptive immune receptor (AIR) large language models, as well as references for studies aiming to identify clones related to particular disease states.

We are now delighted to release the final installment of our natural AIR database series: introducing OAS-nano. This project was enabled by key collaborative contributions from Klara Kropivsek Brumat and Ario de Marco at the University of Nova Gorica and our industrial partners at AstraZeneca: Olga Obrezanova, Erwin de Genst, and Rebecca Croasdale-Wood.

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The First OpenBind Blind Challenge

At OpenBind, we’re working to generate large-scale, open experimental datasets of protein-ligand structures and binding measurements to support the development and evaluation of computational methods for drug discovery. One thing I’m particularly excited about is using these data not just for retrospective benchmarking, but for prospective, blind evaluation.

So, I’m very pleased that we’re launching the first OpenBind blind challenge on 14 October 2026, in partnership with OpenADMET and the ASAP Discovery Consortium. The interim submission deadline is 11 November, with final submissions due by 16 December 2026 at 23:59 UTC.

The challenge asks participants to predict protein-ligand complexes of 400 compounds bound to Zika virus NS2B-NS3 protease, ranging from small fragments to larger, lead-like molecules.

A key challenge will be using the structural information that already exists to accurately predict the binding modes of new, unseen ligands. There are already a number of publicly available structures of Zika NS2B-NS3 protease in the PDB that participants can use.

We’re also setting a high bar for success. While many protein-ligand benchmarks use an RMSD threshold of 2 Å, we’re tightening this to 1.5 Å, along with additional checks on interaction accuracy (lDDT-PLI > 0.8) and physical validity (PoseBusters validity checks). I’m particularly excited to see how docking, cofolding, and other approaches compare!

If you work on protein-ligand structure prediction, I’d strongly encourage you to join the challenge. You can find all the details, including how to register and join the challenge Discord, in the OpenBind announcement.

Update: We’re now live! Check out the challenge on Hugging Face.

Predicting ADME Properties with Machine Learning: 82% of the Performance From Two Descriptors

A Nature survey of ~1500 scientists reported that more than 70% had failed to reproduce another scientist’s experiments, and 50% had failed to replicate their own (Baker, 2016). This study wasn’t specific to machine learning, but the crisis has its own flavour in computational drug discovery.

One aspect of this is that available datasets have known quality issues, and results built on them can be fragile. MoleculeNet and the Therapeutic Data Commons (TDC) opened drug discovery to a wider ML community, but they’re no longer sufficient for driving further advances (Wognum et al., 2024).

Amongst a number of issues, 71% of molecules in one MoleculeNet dataset (BACE) contained at least one undefined stereocenter (a point where the same atoms can sit in two different 3D arrangements), making it unclear what chemical entity is actually being modelled (Li et al., 2026).

The stakes are high. In 2017, a research group found their cancer-target inhibitor inactive from one vendor and highly active from another. Eventually they traced this to vendors selling different mixtures of the compound’s two 3D forms where only one was active on the target and mechanism they were investigating (Baker, 2017).

Most approved pharmaceuticals are relatively small chemical molecules, typically weighing under 900 g/mol, with most of the rest being biologics. Whilst in Oxford in OPIG over the summer as a UNIQ+ student, I focused on ADME, an aspect of early stage drug discovery, where assays are measured in vitro as a stand-in to predict how a compound will behave in vivo (in the human body) before clinical trials. Absorption (does it enter the body), Distribution (where does it go), Metabolism (how quickly it’s transformed) and Excretion (how quickly it’s eliminated) are processes critical to whether a candidate succeeds. 

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Beyond the Vaccine: AI’s Expanding Role in LNP mediated Drug Delivery

Lipid nanoparticles (LNPs) have evolved from a specialised drug-delivery technology into a cornerstone of modern medicine. Their success became evident during the COVID-19 pandemic, enabling the delivery of the mRNA used in the Pfizer-BioNTech and Moderna vaccines. However, their applications extend far beyond vaccination, as LNPs can also deliver siRNA, plasmid DNA and gene-editing machinery, creating opportunities to treat genetic diseases, cancer and many other conditions.

Yet a fundamental challenge remains: how do we design an LNP that delivers the right payload, to the right cells, in the right place?

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A Golden Age of Nanomedicine

As someone who spent their entire academic career, from B.Sc. to M.Sc. to Ph.D., within a Kavli Institute for Nanoscience Discovery (first in Delft and now in Oxford), I’ve had the privilege of seeing firsthand just how beautifully intricate the nanoscale world can be. Now, as my research focuses on lipid nanoparticles for genetic therapeutics and vaccines, I would like to use this platform to advocate for what I believe is one of the most transformative frontiers in modern medicine: the rational design of nanomaterials for therapeutic delivery.

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A first for PROTACs

Last week marked a major milestone in small-molecule drug discovery with the first FDA approval of a proteolysis targeting chimera (PROTAC). After a modest but successful phase 3 clinical trial demonstrated a 2.9 month improvement in median progression free survival1 for a type of advanced breast cancer1, the FDA has approved Veppanu (vepdegestrant), co-developed by Arvinas and Pfizer, as the first PROTAC protein degrader therapy2. So what is a PROTAC?

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SigmaDock: untwisting molecular docking with fragment-based SE(3) diffusion

Alvaro Prat, Leo Zhang, Charlotte Deane, Yee Whye Teh, & Garrett M. Morris
International Conference On Learning Representations (ICLR 2026)

Molecular docking sits at the heart of structure-based drug discovery. If we can reliably predict how a small molecule binds in a protein pocket, we can prioritize compounds faster, reason about interactions more clearly, and build better pipelines for hit discovery and lead optimization. But in practice, docking is still a difficult problem: classical methods are often robust but imperfect, while recent deep learning approaches have sometimes looked promising on headline metrics without consistently producing chemically plausible poses.

SigmaDock was built to address exactly that gap. Instead of treating docking as a problem of directly diffusing on torsion angles or unconstrained atomic coordinates, SigmaDock represents ligands as collections of rigid fragments and learns how to reassemble them inside the binding pocket using diffusion on SE(3)\text{SE}(3). In plain English: rather than trying to “wiggle” every flexible degree of freedom in a tangled way, SigmaDock breaks the ligand into chemically meaningful rigid pieces and learns where those pieces should go, and how they should reorient, to recover a valid bound pose.

Figure 1: Illustration of SigmaDock using PDB 1V4S and ligand MRK. We create an initial conformation of a query ligand where we define our mm rigid body fragments (colour coded). The corresponding forward diffusion process operates in SE(3)m\text{SE}(3)^m via independent roto-translations.
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Design your very own drug: An introduction to structure-based small molecule drug design

Are you curious about how scientists design small molecules to treat disease using computational tools, but the words RDKit, docking, and QED mean nothing to you? Look no further than these tutorials for learning the fundamentals of computational small molecule drug design through interactive tutorials that introduce the key tools, concepts, and workflows. From generating compounds to evaluating their drug-likeness and binding potential, by the end you’ll be ready to explore how computational methods can result in the discovery of your very own (virtual) drug candidates to cure Zika!

Find the materials here: https://github.com/oxpig/dtc-struc-bio-smolecules/tree/main.

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Nanobodies® galore in Utrecht

At the end of September, I had the opportunity to present at the 4th Single-Domain Antibody (sdAb/VHH) Conference hosted in the city of Utrecht. The sdAb conference is a biennial event, and was held for the first time in Bonn (2019), then in Brussels (2021) and Paris (2023), before coming to the Netherlands this year.

This was the first time I’d attended a VHH-focused conference, and I was taken aback at just how large the community is; the Jaarbeurs ‘Supernova’ event hall was completely sold out, with over 400 researchers in attendance (pictures below courtesy of the organisers). The buzz reflects the ever growing interest in sdAbs as tools to discover new fundamental biology, vectors for diagnosing disease, and as prophylactic or curative therapeutics. Most every disease indication was represented at the conference, from anticancer and antiviral sdAbs to antivenom sdAbs (both for use in lateral flow tests to diagnose the snake that bit you, and as quick ‘epipen’-like therapeutics accessible even in the most remote parts of the world).

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Reflections on GRC CADD 2025: A Week of Insight, Innovation, and Baseball

Henry

Back in July, some very lucky OPIGlets ventured across the pond to discover life in Southern Maine (and Boston!). For someone visiting Boston for the first time, no trip would be complete without a Red Sox game—a thoroughly enjoyable highlight (see Figure 1). While we were there, we also went to Gordon Research Conference (GRC) on Computer Aided Drug Design (CADD).

A flock of OPIGlets taking in the Fenway Park experience at a Red Sox game.
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