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Chemoproteomics mass spectrometry in drug development
For discovery, development, and pre-clinical phases of drug development, chemoproteomics supports high throughput screening to identify poor candidates earlier in the pipeline. The specificity of mass spectrometry enables individual proteins and proteoforms to be quantified with high precision and accuracy which is invaluable when quantifying proteins across the entire cellular proteome. Thermo Scientific Orbitrap mass spectrometers expedite the discovery phase of drug development.
Technology innovations to drive productivity and true measurements
Comprehensively study drug-dosed model systems with unbiased interrogation
Meet productivity needs to serve accelerated drug discovery and development. Orbitrap platforms provide throughput, proteome depth, and quantitative precision and accuracy.
Throughput
Modern drug discovery requires the ability to screen 1,000s or 10,000s of drug candidates in model systems under various conditions (dosage concentrations, treatment times, cell types) to determine drug binding selectivity to targets, potency or stability.
Experience high throughput analysis while maintaining depth of proteome coverage with Thermo Scientific Orbitrap Astral Series Mass Spectrometers, Thermo Scientific Orbitrap Excedion Pro Mass Spectrometers, and Thermo Scientific Orbitrap Exploris Mass Spectrometers.
Maintain data quality and seamless user experience with the Thermo Scientific Vanquish Neo UHPLC System direct injection workflow which enables maximum throughput.
Proteome depth
In chemoproteomics, achieving extensive proteome depth is essential for comprehensive drug target identification across diverse biological contexts. This allows for the detection of both high and low abundance protein targets, including rare or transiently expressed proteins, and helps uncover potential off-target interactions for assessing drug safety.
Orbitrap-based mass spectrometers exceed 10,000+ proteins per experiment to enable comprehensive profiling of protein drug targets or off-targets.
Quantitation
Achieving reproducible measurements across and within experiments requires precise and accurate quantitation of protein drug targets at all abundance levels. To avoid unreliable conclusions, this capability is essential for distinguishing true protein-drug interactions from false positives or artifacts.
Orbitrap-based mass spectrometers offer precision and accuracy of quantitation through known ratio assessment of global proteome measurements of mixed species in a single experiment.
Robustness
To help ensure optimal data quality and efficiency for large-scale projects, our instruments have been tested over months of data generation to confirm stable performance levels. Orbitrap instruments offer easily accessible column and emitter interfaces, ion inlet surfaces that can be changed in minutes, and simple automated calibration routines to make instrument operation straightforward. Benefit from consistent and robust performance across a high volume of injections.
Robust and reproducible chromatographic separations over extended periods with Vanquish Neo UHPLC System
Chemoproteomics in drug discovery
Mass spectrometry plays a key role for proteomic analysis throughout the stages of drug development from discovery screening to lead validation and optimization and preclinical assay development.
Discovery screening
Activity based protein profiling (ABPP) methods have used TMT and Thermo Scientific Orbitrap Ascend Tribrid MS to measure protein reactive sites as potential targets for drug binding. This can include the enrichment of peptides that contain surface accessible reactive sites or pockets. Changes in detection of these protein reactive sites can reflect drug binding specificity and strength and this workflow is used for screening covalent compound libraries. TMT multiplexing enables larger screening projects and provides excellent quantitative accuracy and precision when combined with Orbitrap Tribrid MS.
What customers are saying about Orbitrap Ascend Tribrid MS
Targeted protein degradation (TPD) relies on induced proximity to use cellular machinery to eliminate a protein of interest (POI). Data independent acquisition (DIA) with the Orbitrap Astral Series Mass Spectrometers supports screening 100s of samples per day with full proteome coverage to measure degradation and survey for off-target effects. Examples include PROTACs, LYTACs and molecular glues as types of compounds that can bring two or more proteins together, resulting in POI degradation by the proteasome or lysosome.
Thermal protein profiling (TPP) relies on changes in protein stability as a result of drug engagement (covalent or non-covalent). Quantitative accuracy of Orbitrap MS instruments enables reliable detection of small changes from early lead compounds and off-target hits. Profiling changes in a protein’s melting profile during treatment with a drug can provide an early readout on drug specificity and potential off-target proteins. TMT reagents allow for multiple melting curves in a sample, streamlining analysis and increasing the speed of screening.
What customers are saying about TPP and Thermo Scientific products
Lead validation
Lead optimization, validation, and cell biology insight are critical phases of the drug discovery process towards MoA. The data quality from Thermo Scientific MS instruments generates reliable conclusions on target specificity and quantification. This insight from MS proteomic experiments early in the pipeline can increase the success rate for drug candidates during clinical trials. There are several proteomic assays and LCMS methods that can provide insight towards validation and MoA. Thermo Scientific mass spectrometers provide leading sensitivity and dynamic range performance, benefiting experiments for protein turnover rates, post translational modification analysis, protein-protein interaction studies, and competitive binding assays.
Thermo Scientific chemoproteomics workflows
What are customers saying about Orbitrap Astral MS
Nagarjuna Nagaraj
High throughput DIA workflows for maximum throughput with deep proteome coverage
With exceptional depth of proteome coverage of 10,000+ proteins, Orbitrap platforms maintain quantitative precision and accuracy with data-independent acquisition (DIA) analytical workflows. Technology advancements, including the Orbitrap Astral Series Mass Spectrometers, have enabled increased throughput of analysis with higher sensitivity while maintaining accurate and precise quantitation.
Activity-Based Protein Profiling (ABPP) is well-suited for TMT multiplexing to achieve precise peptide-level quantitation. With targeted protein degradation (TPD) workflows, high or low abundance protein degradation products can be accurately detected and quantified to comprehensively assess drug specificity for desired or off-target proteins of interest.
Results from TPD screening using the PROTAC ARCC-4 in VCaP cells, employing narrow-window DIA (nDIA) with the Orbitrap Astral Mass Spectrometer. Excellent proteome coverage was achieved with over 8,300 proteins quantified at less than 5 min instrument time per sample. Using a 60 min gradient, over 10,000 proteins were quantified enabling detection of low-level proteins. The volcano plot shows the PROTAC specificity with only two proteins degraded after cells were treated with ARCC-4, including the primary target, androgen receptor. Table displaying consistent half-maximal degradation concentration (DC50) values and R-squared values for curve fitting, with flexible throughput options (SPD).
Sample multiplexing analysis with TMT for complete experiments in a single injection
Orbitrap mass spectrometers deliver exceptional mass accuracy and resolution, enabling multiplexing of up to 35 samples using TMT labeling reagents. Multiplexing can support higher sample throughput and deeper peptide coverage when combined with peptide fractionation. Tribrid Mass Spectrometers, including the Thermo Scientific Orbitrap Eclipse Tribrid Mass Spectrometer and Thermo Scientific Orbitrap Ascend MultiOmics Mass Spectrometer, offer unique SPS MS3 acquisition strategies. These are supported by real-time search acquisition to enable unmatched accuracy and precision of quantitation for TMT experiments.
Activity-Based Protein Profiling (ABPP) is well suited for TMT multiplexing to achieve precise peptide level quantitation. With TPP or PISA investigations, TMT multiplexing reagents can be used to combine different temperature points, multiple drugs Using TPP or PISA investigations, TMT multiplexing reagents allow the combination of different temperature points, multiple drug candidates, or drug concentrations into a single sample injection. This enables the assessment of protein melting curves for each protein in the cellular proteome within one experiment.
Identification: Real-Time Search data acquisition workflow identifies peptides at the MS2-level and only those identified will be quantified. Quantitation: TMT-labeled peptides are quantified using SPS MS3 on an Orbitrap Tribrid MS providing the most accurate quantitation for TMT studies.
High-throughput targeted screening and quantitation of POIs with PRM workflows
Thermo Scientific mass spectrometers offer robust, sensitive, and reproducible solutions for targeted quantitation to support protein drug target verification or validation. Parallel reaction monitoring (PRM)-based quantitation allows for simultaneous sequence confirmation and targeted quantitation, leveraging full MS/MS spectrum of all fragments while quantifying target transitions. Orbitrap Exploris Mass Spectrometers offer exceptional selectivity, featuring high resolution accurate mass precision with PRM acquisition. The Thermo Scientific Stellar Mass Spectrometer offers high sensitivity and scan speed with the unique ability to quantify 100s or 1000s of proteins in a single targeted PRM experiment.
High confidence drug metabolite profiling, identification and characterization
Drug metabolism and pharmacokinetics (DMPK) are an essential part of the drug development cycle. The exceptional sensitivity and high-quality MS/MS and MSn spectra from Orbitrap Exploris and Orbitrap Tribrid Mass Spectrometers enable confident detection and structure elucidation of small molecule drug metabolites, including chimeric modalities of PROTACs or molecular glue drug candidates.
Intelligent data acquisition available on Orbitrap Tribrid Mass Spectrometers, including Thermo Scientific AcquireX Data Acquisition Workflow and real-time library search, streamline the acquisition of sample relevant MS² and MSⁿ data for comprehensive drug metabolite profiling. Thermo Scientific Compound Discoverer Software, helps to ensure confident compound identification and structural elucidation for pharmaceutical metabolism studies in an automated manner.
Five abundant metabolites were identified from the PROTAC drug MZ1 using Orbitrap Tribrid MS analysis and Compound Discoverer Software.
Protein-ligand structure validation
Unlike traditional methods that might require protein crystallization, protein-ligand structure validation using mass spectrometry can provide the following information: native mass spectrometry (nMS)-allows researchers to directly observe and characterize protein-ligand complexes in their native state by measuring the mass-to-charge ratio of the complex. Crosslinking, protein footprinting and HDX-MS are enabling the assessment of binding stoichiometry and providing insights into the interaction between the protein and ligand without disrupting non-covalent bonds involved in the complex formation.
Complete set of structural proteomics tools
High-Throughput Ligand Screening via Gas Phase Affinity Selection Native Mass Spectrometry
Gas phase affinity selection native mass spectrometry utilizes an integrated LC system coupled to Orbitrap MS to streamline rapid online buffer exchange, parallel compound binding, and direct native MS analysis of complexes. MS1 identifies binding complexes, MS2 determines bound ligands, and MS3 elucidates unknown ligands, significantly enhancing screening throughput and depth.
Additional resources to learn more
For Research Use Only. Not for use in diagnostic procedures.