Rahul Baghla is a research scientist with over 15 years of experience in diverse mass spectrometry applications, delivering value to the pharmaceutical and biopharmaceutical industries.
CREDIT: Rahul Baghla, SCIEX
Modern drug discovery relies on the identification and optimization of molecules that can specifically modulate the activity of enzymes or receptors, known as drug targets. Achieving this requires assays capable of efficiently screening large compound libraries, and selecting the right readout technology is crucial for success.
Mass spectrometry (MS) has become an established option for powerful analytics, offering rapid analysis of enzymatic activities by directly quantifying product formation based on mass-to-charge (m/z) differences between substrates and products. Compared to traditional readout methods like fluorescence or UV absorbance, MS provides a label-free, highly versatile approach that is less prone to interference from optical artifacts. It also enables the multiplexed measurement of physiologically relevant biomolecules without relying on artificial probes or custom antibodies.
Anuja Bhalkikar is responsible for conducting customer demonstrations, providing technical support to clients that includes streamlining automation along with the Echo MS+ system, and generating new workflows.
CREDIT: Anuja Bhalkikar, SCIEX
Historically, one limitation of MS in high-throughput applications was its slower analysis cycle times, making it less ideal for high-throughput screening (HTS). However, recent advancements in MS instrumentation have drastically improved scanning speeds, making it a viable solution for fast-paced screening. To explore how these innovations are reshaping drug discovery, Drug Discovery News spoke with Rahul Baghla, Senior Manager of Global Scientific Marketing and Echo MS® CoE at SCIEX, and Anuja Bhalkikar, Senior Scientist at the SCIEX Echo® MS Center of Excellence. They shared their insights into how acoustic ejection mass spectrometry (AEMS) is advancing MS technology, driving faster and more efficient high-throughput screening.
What challenges in HTS are driving scientists to explore alternatives to traditional techniques?
Rahul: HTS is essential in drug discovery because it enables the examination of thousands of compounds each week to find potential drug candidates. Traditional methods, like plate readers, lack the selectivity required for precise and accurate results. Although liquid chromatography-mass spectrometry (LC-MS) overcomes this issue, its throughput limitations can slow down the discovery process. Consequently, scientists are continually searching for more efficient and precise HTS methods to speed up drug discovery.
Anuja: While LC-MS is the gold standard for analysis in drug discovery workflows, it requires long analysis times, making it challenging in a high-throughput setting. Further, DMSO-based samples cannot be directly analyzed, requiring cumbersome dilution steps that further slow down the process.
What advantages does AEMS offer in terms of speed and sample throughput?
Rahul: AEMS provides significant advantages in terms of speed and sample throughput. Designed to operate at the speed of a plate reader, AEMS can achieve an analysis speed of one sample per second, greatly accelerating workflows. Additionally, AEMS bridges the gap between speed and accuracy, providing precise and selective analysis when integrated with systems like the ZenoTOF 7600 system. This combination makes AEMS a powerful tool for scientists.
Anuja: AEMS allows fast and accurate sample readout along with the ability to analyze samples directly from DMSO in either 384 or 1536 well formats. AEMS analysis also tolerates the presence of water in these DMSO samples, permitting the user to analyze aged libraries.
The addition of electrospray ionization ensures effective ionization of a wide range of analytes. Plus, the Echo® MS+ system offers two MS options and seamlessly integrates with existing automation systems and data platforms, ensuring minimal disruption to workflows.
The Echo MS+ system gives you high-quality data, analytical flexibility and high sample throughput.
CREDIT: SCIEX
What limitations exist with fluorescence-based screening, and how can MS-based methods address these challenges?
Rahul: Fluorescence-based screening methods face several significant challenges. One of the primary issues is high background noise from autofluorescence, which can result in false positives.
MS-based techniques provide label-free detection, which significantly reduces background interference. This label-free approach enhances the selectivity and sensitivity of the analysis, making MS-based methods particularly effective for both small and large-molecule drug discovery.
Why is automation essential in modern drug discovery workflows?
Rahul: Automation is essential in modern drug discovery workflows because it enhances overall efficiency by seamlessly integrating sample preparation, data acquisition, and data management. Automated systems accelerate repetitive, time-consuming tasks, significantly reducing human error and ensuring more precise and consistent results. These improvements are crucial for an effective drug discovery process, enabling faster and more reliable development of new therapies.
How is the role of mass spectrometry evolving to help reduce time-to-market for new therapeutics?
Rahul: Mass spectrometry is becoming increasingly crucial in speeding up the development of new therapeutics, particularly with the emergence of novel drug modalities. MS techniques can quickly deliver comprehensive data essential for the detailed characterization of complex molecules. Continuous innovations, such as Electron Activated Dissociation (EAD) in the ZenoTOF 8600 system and ZenoTOF 7600 system, have shown a remarkable ability in producing distinctive MS/MS fragments. These fragments provide deeper insights into the structure and sequence of new drug modalities and their metabolites, which is vital for understanding drug toxicity.
What’s one common concern about adopting AEMS in drug discovery, and how do you help scientists address it?
Rahul: One common concern about adopting AEMS in drug discovery is the sheer volume and speed of data generation. This technology produces vast amounts of information very quickly, which can be overwhelming to manage and analyze effectively.
To address this, it is crucial to implement an automated solution for data management. AI Quantitation software is an excellent tool for this purpose. It helps scientists efficiently process and analyze the data, ensuring accurate calculation of biologically relevant endpoints. This not only streamlines the workflow but also enhances the reliability and speed of drug discovery processes.
Anuja: As with the adoption of any new technology, the concern is if it will disrupt existing workflows. The SCIEX team at the Echo® MS+ system Center of Excellence is available to demonstrate how to incorporate it seamlessly, assist with assay development, and train the team in the lab. In addition, steps in the process are interchangeable between the technologies for a streamlined solution.
What’s the most exciting innovation you’ve seen in mass spectrometry for drug discovery?
Rahul: The most exciting innovation in mass spectrometry for drug discovery that I've come across is the Echo® MS+ system. This system uses AEMS to enable ultra-fast, high-throughput screening by transferring tiny sample droplets into the mass spectrometer without contact. This speeds up analysis, reduces contamination, and provides highly sensitive and accurate detection of both small and large molecules. The system's versatility in handling various sample types makes it an invaluable tool for drug discovery, transforming the process by making it faster, more accurate, and efficient.
