How an AI drug discovery collaboration between Nxera and PharmEnable is accelerating complex science: generating new hit molecules against a difficult GPCR target

Artificial Intelligence (AI) is becoming an increasingly important part of drug discovery – as demonstrated by the significant progress in the ongoing collaboration between Nxera and PharmEnable focused on a challenging peptidergic G protein-coupled receptor (GPCR) target associated with neurological disease.

The collaboration brings together Nxera’s expertise in GPCRs with PharmEnable’s AI technology and has greatly accelerated the usual timelines for such a project. Matt Barnes, VP Drug Discovery at Nxera, and James Dale, Director of Chemistry at PharmEnable, tell us more.


What are some of the challenges traditionally associated with drug discovery against this target?

Matt Barnes: It is important to understand first that the natural agonist ligand of a peptidergic GPCR is a large, complex peptide and this is often very difficult to block with a small molecule, particularly one that has properties suitable for development as a therapeutic agent for neurological disease.

James Dale: Traditionally, identification of target hits has come from high throughput screening of large physical screening libraries, or by virtual screening and targeted selection of molecules for purchase, and screening from commercially available collections. Often it can take a significant amount of time and money to find the right chemical matter within those libraries that can then be optimized successfully.

Matt Barnes: For this particular target, these challenges are exacerbated due to the target also being in the central nervous system (CNS), consequently posing additional challenges of finding compounds that can penetrate the CNS. Hence our collaboration with PharmEnable aims to address specific challenges of peptidergic GPCR drug discovery, namely access to novel drug-like chemical space and exploration of molecules in this space that are compatible with the target and tractable for drug discovery, by taking a more technology-driven approach.


Why were the Nxera and PharmEnable teams complementary for tackling these challenges?

Matt Barnes: The Nxera team has assembled a wealth of structural and ligand-binding information on the selected target with their world-leading GPCR-targeted StaR® technology and structure-based drug design (SBDD) capabilities. The team had created several promising molecules against this target and needed to identify compounds with sufficiently desirable neurological drug-like properties to advance into preclinical studies.

James Dale: PharmEnable’s platform can uncover unexplored parts of the chemical universe to find novel and specific hits for currently challenging targets.

First, the combination of PharmEnable’s chemSAILOR with Nxera’s StaR® technology and SBDD capabilities guides the identification of the chemical space required by the target.

Second, PharmEnable’s chemUNIVERSE provides access to novel, synthetically accessible molecules that are not commercially available or similar to known bioactive molecules.

Third, PharmEnable’s chemSEEK AI, cheminformatics and computer aided drug design (CADD) toolbox combined with Nxera’s state-of-the-art GPCR scoring methods, identifies the best molecules among the de novo generated molecule library to set for synthesis.

Overall, the approach combines advanced medicinal chemistry expertise and cutting-edge AI/computational methods to efficiently sample new regions of the chemical space, perhaps where no drug-like ligands have previously been identified.

“Using PharmEnable’s technology to efficiently and rapidly explore the relevant chemical space, we have significantly accelerated novel hit identification.”

Matt Barnes, VP Drug Discovery


What impacts have you seen so far from the collaboration?

Matt Barnes: The collaboration has significantly accelerated novel hit identification by using PharmEnable’s technology to efficiently and rapidly explore the relevant chemical space. After the joint scientific team selected a small number of molecules for synthesis, we have identified a set of novel small molecules against this GPCR target, which are currently progressing through hit-to-lead optimization.

What are the next milestones for the collaboration?

James Dale: The next milestones will include optimizing the hit molecules to have the required selectivity profile for tackling the complex biological setting associated with the disease indication we are targeting, as well as ensuring the molecules have the best pharmacology profile to be efficacious and safe to progress to the clinic.

Learn more about GPCR targets and their importance in our In Focus article.