Affinity Selection Mass Spectrometry (AS-MS): A Smarter Path to High-Quality Hits for Drug Discovery

While traditional high-throughput screening (HTS) has delivered thousands of hits since its inception, this technique also comes with significant limitations – assay development can be slow and costly, labels or reporters may interfere with the natural behavior of proteins, and many hits originate from flat, over-represented scaffolds that crowd IP space and limit developability.

Affinity Selection Mass Spectrometry (AS-MS) presents a more innovative method. By detecting direct, label-free interactions between proteins and small molecules in solution, ASMS offers a faster, cleaner, and more versatile way to identify true binders, especially against challenging targets.

What is AS-MS and how does it work?

AS-MS is built on a simple yet powerful principle: if a small molecule binds to a protein, mass spectrometry can detect it.

Incubation: The protein of interest is incubated with a diverse library of small molecules under near-native conditions.
Separation: Bound compounds are separated from unbound ones by ultrafiltration, size-exclusion, or affinity capture methods.
Detection: Mass spectrometry identifies the bound ligands directly, without any chemical labels or reporters.
Analysis: Data processing distinguishes true binders from background noise, producing a shortlist of compounds for confirmation.

Because AS-MS analyzes complex mixtures directly, it can be used to screen thousands to millions of compounds quickly, consuming only small amounts of protein and compound.

How does AS-MS compare to other HTS methods?

Method	Strengths	Limitations
Fluorescence / Reporter-Based HTS	Extremely high throughput (hundreds of thousands of wells per campaign); Established infrastructure and relatively low per-well costs.	Requires extensive assay development; Labels can distort binding; High false-positive/negative rates; Less suitable for complex or multi-protein targets.
Biochemical / Enzymatic Assays	Provide functional activity readouts; Direct measurement of catalytic modulation.	Require known enzymatic function; Unsuitable for non-enzymatic proteins or protein–protein interactions; Prone to compound interference.
DNA-Encoded Library (DEL) Screening	Very large chemical space (billions of compounds); Efficient for soluble, immobilizable proteins.	Libraries are often biased toward flat, simple scaffolds; Hits require resynthesis and validation; Protein immobilization can distort biology; Follow-up SAR space is often limited.
Affinity Selection Mass Spectrometry (AS-MS)	Label-free and native: No need for fluorescent tags or immobilization of target. Versatile: Works with soluble proteins, PPIs, complexes, membrane proteins, and other difficult targets. Efficient: Low protein/compound consumption, and amenable to direct-to-biology approaches; screens can be completed in a matter of weeks. Clean data: Mass-based detection reduces artifacts. Medicinal chemistry-ready: Hits are real, tangible molecules, ready for hit expansion.	Measures binding, not function: Follow-up assays needed to confirm activity; Throughput lower than ultra-HTS plate formats; Particularly large or unstable targets may require assay optimization.

Why partner with Edelris for your next AS-MS project?

Although AS-MS appears conceptually simple, it is multi-parametric, and no single method fits every protein. Edelris’ strength lies in the expertise and assay development discipline we bring to each project.

Before the first screen, our scientists invest time upstream to fully optimize conditions, laying the groundwork for downstream success. Through proof-of-concept experiments, we quickly determine whether a target is suitable for AS-MS or whether another approach will deliver better value (and advise you accordingly).

We also draw on a range of versatile approaches, including Automated Ligand Identification System (ALIS), SpeedScreen, competition assays, and differential or mixed-mode screening to match assay design to each biological question. Once a project workflow is established, quality control is integrated at every stage to check the consistency of each test, not only validating the conformity of the MS analysis, but also the library and target quality.

Edelris provides precision through data science

Since 2023, Edelris has implemented a proprietary in-house data platform incorporating the latest cloud-based tools to manage, analyze, and visualize AS-MS results. The analysis of MS chromatograms can be a complex task when dealing with mixtures of hundreds of compounds, sometimes at very low concentrations, and demands exceptional analytical rigor. Our data scientists and analytical chemists pay special attention to signal quality (including mass error, retention time stability, and isotopologues), while statistical analysis mobilizing the history of screening data on several targets help identify anomalies and focus on reliable data (by ruling out systematic false positives, for example).

How does Edelris’ chemistry make the difference?

AS-MS is a powerful standalone technique. However, when paired with the right chemical library, it becomes transformative.

At Edelris, we carry out AS-MS screens using our proprietary Keymical Space™, a collection of over 2 million compounds designed to go beyond conventional chemistry. Unlike many commercial libraries, Edelris’ Keymical Space is:

Natural product-inspired: Our scaffolds echo nature’s proven ability to modulate biological targets.
3D-enriched: High sp³ content and stereochemistry improve fit and selectivity.
Medicinal chemistry-driven: Enumeration guided by drug-like physicochemical properties, attractive pharmacophores, and scaffold diversity.
Synthesis-validated: Every compound is tangible and tractable. Hits can be resynthesized, analogued, and optimized quickly.
Rich sub-library collections: Including fragments, covalent binders, and molecular glues.

The end result is that ASMS hits from Edelris provide you with smarter starting points – differentiated scaffolds, biologically relevant interactions, and clear SAR potential.

What are the other advantages of carrying out ASMS screening with Edelris?

Rapid hit discovery: Fast track assay development, since AS-MS methods are solution-based and do not require immobilization steps.
Limited false positives, accelerating direct ligand identification via high-resolution mass detection and optimized screens.
Our screening deck is assembled without any chemistry limitations, as the compounds do not need any additional or labile tags.
Novel chemistry: Access a unique, 3D-rich, natural product-inspired 2M-compound library distinct from DEL and other more widely available commercial decks.
High flexibility in decks to be screened: AS-MS is suitable for screening a broad range of chemical libraries, including macrocycles, peptides, or natural products. Besides our in-house screening deck, you can also opt to have Edelris screen your own compound libraries.
Target versatility: Ideal for PPIs, GPCRs, RNA, ion channels, transcription factors, molecular glues, membrane proteins, and other “hard-to-drug” targets.
Cleaner IP space: Unique scaffolds mean more freedom to operate and stronger differentiation.
Integrated progression: The entire process is performed in Edelris’ laboratories, from target qualification to hit expansion, SAR design, route scouting, and scaffold hopping, ensuring that promising binders advance rapidly toward quality leads.

Go further, faster – Edelris combines the versatility of AS-MS with the power of computational chemistry

To boost the power of our AS-MS platform, we have enumerated a 50 million-compound virtual library from our 3D-rich Natural Product-inspired Keymical Space. This virtual collection is rule-of-5 (Ro5) compliant, enriched with attractive pharmacophores and original decorations, and features an unmatched diversity and novelty. Explore plausible binding modes of AS-MS hits in silico, accelerate hit expansion using structure-guided drug design, and rapidly confirm affinities experimentally with AS-MS profiling. Our team of experienced medicinal chemists stay tightly connected to the process, ensuring hits can be rapidly synthesized, validated, and optimized, accelerating the Design-Make-Test-Analyse (DMTA) cycle and delivering better lead compounds faster.

In a landscape crowded with flat commercial libraries and DEL collections that often produce impractical hits, Edelris delivers something different:

Expert assay design and validation: Multiple screening modes and flexible, project-specific solutions. Because AS-MS success begins upstream.
Smarter chemistry: Creative, 3-D rich, natural product-inspired scaffolds.
Better hits: Label-free ASMS delivers true binders with fewer artifacts.

Faster progression: Hits are tangible, tractable, patentable, and directly enhanced by our medicinal chemistry expertise.

If you are tackling challenging biology, exploring novel mechanisms, or seeking higher-quality starting points, Edelris’ AS-MS platform offers a smarter, faster way forward.