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SAMDI ASMS: More Than Seeing What Sticks
A Q&A with Science Director Zack Gurard-Levin on how SAMDI technology is advancing and accelerating small molecule drug discovery
Charles River Chicago, previously SAMDI Tech Inc (acquired by Charles River in January 2023), provides a broad scope of hit identification and drug discovery research solutions. The Chicago site is home to the proprietary label-free and high-throughput SAMDI mass spectrometry (MS) screening platform, a leading assay for measuring biochemical activities (SAMDI MS) and binding interactions (SAMDI ASMS) for virtually any target.
The SAMDI technology combines surface chemistry and MALDI TOF mass spectrometry to offer critical solutions to enhance and accelerate drug discovery from assay development and high-throughput screening through potency determination, including eliminating false-positive and negative results from optical interference. It offers multiplex capabilities, and is the only MS approach amenable to any buffer component without limitation.
The new team recently transitioned into a larger research facility, custom-designed to support automation and efficiency and to streamline workflows for SAMDI technology and assay methodologies that go beyond label-free. We talked to Dr. Zack Gurard-Levin, Science Director at Charles River Chicago, about the small molecule discovery solutions his team brings to the portfolio.
How does SAMDI ASMS overcome the challenges of conventional ASMS techniques?
Zack: Many of the originally described affinity selection mass spectrometry, or ASMS, workflows involve a multi-step process that limits throughput. To address this challenge, researchers often test hundreds or thousands of small molecules in a single reaction, which opens opportunities for compound misbehavior and thereby higher false-positive hit rates. The SAMDI ASMS workflow benefits from the rapid and specific immobilization of complexes on the SAMDI biochips, eliminating the slower chromatography steps. The accelerated workflow therefore allows the screening of smaller pool sizes (eight compounds per reaction) which minimizes compound misbehavior and leads to higher validation rates, while still screening millions of compounds in a matter of days.
What types of targets can be screened using SAMDI ASMS?
Zack: SAMDI ASMS is amenable to virtually any target, including proteins, complexes, and oligonucleotides such as RNA. One of the critical solutions of the SAMDI technology is that, unlike other mass spec approaches, it is amenable to any buffer without limitation. This flexibility is due to the rapid and specific immobilization of the analytes of interest, while all other components are simply washed away, eliminating the ion suppression observed with other MS techniques and generating high-quality, decision-driving data. SAMDI ASMS is amenable to detecting non-covalent small molecule binders and other ligands including peptides, oligonucleotides, and lipids, which opens avenues for competition studies to inform on the binding site location.
In addition to ASMS, where else has the SAMDI technology been able to revolutionize small molecule drug discovery?
Zack: The SAMDI technology was first described by Milan Mrksich to overcome the challenges of traditional biochemical assay methods, most notably the requirement for labels. SAMDI mass spec offered the first label-free and high-throughput alternative, and a flexibility amenable to characterizing hundreds of enzyme activities. SAMDI mass spec also offers multiplex opportunities where two or more enzymes can be screened simultaneously, saving on reagent consumption, multiplying the data generated in a fraction of the time, and a data-rich output to inform on potency and selectivity. The ability to accommodate any buffer component is a unique solution compared to traditional MS approaches and encourages researchers to optimize their assays according to the needs of the target, rather than forcing compromises to utilize the MS instrument, generating the highest data quality to give scientists the confidence needed to make critical go/no-go decisions.
What are the advantages of using SAMDI technology over traditional biochemical assays?
Zack: It is a real testament to the technology and its flexibility that more than two decades later, it continues to be a game changer in drug discovery. For example, in the last few years, we have seen an increasing interest in chemically induced proximity mechanisms, such as targeted protein degradation through proteolysis targeting chimeras and molecular glues. Identifying compounds that bind to structured RNAs is another exciting drug discovery strategy. The SAMDI ASMS platform is ideally suited to initiate drug discovery efforts for these targets, and within Charles River Discovery we can then develop and optimize those compounds to demonstrate that they exhibit the desirable mechanistic effect in cellular assays and beyond. More recently, we are working to apply SAMDI ASMS to identify small molecules that bind to cell surface receptors by combining SAMDI technology with the capabilities of the Retrogenix® platform, opening new label-free and high-throughput small molecule drug discovery solutions for GPCRs, ion channels, and other receptors. We are really excited to see this innovation develop and bridge the gap from the biochemical to the cellular setting.
In addition to SAMDI MS and ASMS, can you tell us about some of your other on-site capabilities?
Zack: The Chicago site is a comprehensive drug discovery solutions provider with extensive expertise in biochemistry, chemistry, molecular biology, enzymology, drug discovery, and more. In addition to SAMDI, we offer traditional assay methodologies including optical readouts (fluorescence, luminescence, HTRF/TR-FRET, and AlphaLisa, among others), a dedicated radioactivity lab, and a tissue culture facility. We also have an in-house, world-class collection of over a half million diverse, pharmacophore-like compounds amenable to screen any target with any methodology. The library is available as individual molecules for biochemical assays (SAMDI mass spec or beyond label-free approaches) and a compressed format in pools of eight specifically for SAMDI ASMS.
Learn more about how SAMDI MS and ASMS are accelerating drug discovery for challenging targets and reach out directly to our hit identification team to start a conversation.