High-Throughput ASMS Screening in Drug Discovery & Development

What is high-throughput ASMS screening?

Affinity selection mass spectrometry (ASMS) is Momentum’s flagship high-throughput screening service for non-covalent drug discovery and development. This powerful technology enables the high-throughput screening of compound libraries against proteins, multi-protein complexes, and RNA/DNA oligos. Identified hits can be readily developed into potent therapeutics, including targeted protein degraders, molecular glues, and other next-generation modalities.

At Momentum, we leverage the Automated Ligand Identification System (ALIS) platform for high-throughput ASMS screening. In this approach, targets are first incubated in solution alongside compounds of interest. For primary screening efforts, compounds are often screened in pools of 250, enabling 100K compounds to be screened in ~48 hours. In follow-up validation assays, compounds can be assessed in smaller pools, in singleton, or in dose-response format. After incubation, size exclusion chromatography is used to isolate bound complexes from unbound test compounds. Bound compounds are dissociated from their targets via reverse phase chromatography, then subjected to time-of-flight mass spectrometry to reveal their identify and generate a comprehensive list of screening hits.

Click here to learn more about Momentum’s ASMS high-throughput screening services.

How does high-throughput ASMS screening support drug discovery and development efforts?

High-throughput affinity selection mass spectrometry is a powerful tool for hit discovery and validation. As a label-free technology, ASMS avoids the need for bulky, disruptive tags on either targets or compounds. It is compatible with a broad range of target types and requires minimal assay development, reducing set-up needs and turnaround time. ASMS can also provide valuable information about the relative strength of binding affinities, enabling hits to be rank-ordered for further development. For these reasons (and more!), many scientists have found affinity selection mass spectrometry to be a powerful asset in drug discovery and development, leveraging this technology to identify hits for diverse targets across a range of modalities and therapeutic areas.

Below, we’re highlighting two papers from the year so far that harnessed the power of high-throughput ASMS screening to accelerate drug discovery and development research.

Spotlight #1: Identification of a small molecule CAPON binder using affinity selection-mass spectrometry screening (SLAS Discovery)

In March 2026, a team from Weill Cornell Medicine published the discovery and characterization of MA32, a small molecule that binds the protein CAPON. CAPON is an adaptor protein known to regulate neuronal nitric oxide signaling and whose dysregulation has been implicated in a range of neurodegenerative and psychiatric conditions. In an effort to identify small-molecule binders of CAPON with therapeutic potential, researchers performed ASMS using a chemically diverse library of approximately 10,000 drug-like compounds. Of 121 preliminary hits, 52 compounds were selected for additional characterization and optimization. One of these compounds – MA32 – was validated as a robust and reproducible CAPON binder, with structural analysis further elucidating its molecular interactions. The identification of MA32 provides a valuable starting point for the further development of CAPON-targeted small-molecule therapeutics, offering promise for the treatment of Alzheimer’s disease and related pathologies.

Spotlight #2: An Integrative Biophysical and Computational Workflow Uncovers New Allosteric Sites and Modulators of the Human A2A Adenosine Receptor (ACS Chemical Biology)

View ChemRxiv preprint

In April 2026, researchers reported the identification of multiple novel allosteric binders of the human A2A adenosine receptor (A_2AAR) with functional cAMP-modulating effects. This research focused on allosteric ligands, which modulate the activity of a target protein without binding to the protein’s active site. Because ASMS is a binding-site-agnostic approach, it readily identifies allosteric binders for diverse target classes. To identify A_2AAR binders, researchers screened 300,000 compounds in pools of 500, generating 8,367 initial hits. After removing suspected non-specific binders, the team selected 98 compounds for further validation. This list was ultimately narrowed down to five hit compounds (C1-C5), which were characterized through a variety of binding and functional assays. Compounds C1 and C2 were shown to inhibit cAMP production in HEK298 cells, demonstrating their functional effect as A_2AAR modulators. As A_2AAR is known to play an immunosuppressive role in tumor cells, these results are relevant to the development of oncology therapeutics. Furthermore, this work provides a broadly applicable framework for the use of ASMS screening for allosteric binder identification.

How can I access high-throughput ASMS screening services?

ASMS requires mass spectrometry instrumentation that is inaccessible to many research teams. For this reason, scientists often choose to partner with specialized CROs in order to perform ASMS high-throughput screening experiments. This approach has the additional benefit of allowing research teams to benefit from the expertise and practical know-how of ASMS specialists who have significant experience with both typical and modified ASMS workflows.

At Momentum, our scientific team has combined decades of experience performing high-throughput ASMS for diverse pharmaceutical, biopharmaceutical, and biotech clients. In addition to pilot screens, full library screens, and validation assays, our team has developed specialized workflows to enable the effective screening of membrane proteins and molecular glue candidates.

To learn more about how we can accelerate your drug discovery research with high-throughput affinity selection mass spectrometry screening, send us a message and schedule a meeting with our team.

Sources

Abdo AN, Nada H & Gabr M. Identification of a small molecule CAPON binder using affinity selection-mass spectrometry screening. SLAS Discov 40, 100304 (2026).

Prudent R, Ray AP, Thakur N, Moreno A, Tandaric T, Kanonenberg K, Lemoine H, Forcellini E, Cecon E, Roche D, Jockers R, Gutiérrez-de-Terán H & Eddy MT. An Integrative Biophysical and Computational Workflow Uncovers New Allosteric Sites and Modulators of the Human A_2A Adenosine Receptor. ACS Chem Biol (2026).