Mass spectrometry (MS) is a powerful, versatile technique with applications spanning the full spectrum of the drug discovery and development pipeline¹. MS can provide information on the structure, function, activity, stability and interactions of proteins, which are the main targets of most drugs². MS can also be used to quantify drugs and their metabolites in biological samples, monitor drug efficacy and safety, and identify novel biomarkers³. In this article, we will review some of the key MS-based methods and technologies that facilitate the discovery and development of new, effective therapeutics.
Target identification and validation
One of the first steps in drug discovery is to identify and validate a molecular target that is involved in the pathology of a disease. MS can help in this process by enabling the analysis of protein expression, localization, modification and interaction in various biological systems². For example, MS can be used to compare the proteomes of healthy and diseased cells or tissues, revealing potential targets that are differentially expressed or regulated¹. MS can also be used to map protein–protein interactions and protein complexes, identifying key components of signaling pathways or cellular processes that can be modulated by drugs².
One of the emerging MS-based techniques for target identification is chemoproteomics, which involves the use of small molecules or fragments that bind to proteins in a complex biological mixture². These molecules can be either known drugs or compounds with unknown targets, or specially designed probes that contain a reactive group and a tag for enrichment and detection by MS². By analyzing the proteins that are captured by these molecules, chemoproteomics can reveal novel targets or off-targets of drugs, as well as provide information on the binding affinity, selectivity and mechanism of action of the compounds².
Another innovative MS-based technique for target identification is targeted protein degradation, which exploits the ubiquitin–proteasome system to selectively degrade proteins of interest². This technique involves the use of bifunctional molecules, called proteolysis-targeting chimeras (PROTACs), that recruit an E3 ubiquitin ligase to a target protein, resulting in its ubiquitination and degradation². By monitoring the changes in protein abundance and activity after treatment with PROTACs, MS can help to validate the target protein as well as optimize the design and efficacy of the degraders².
Drug metabolism and pharmacokinetics
Once a lead compound is identified and optimized for a target protein, it needs to be evaluated for its pharmacokinetic (PK) properties, such as absorption, distribution, metabolism and excretion (ADME)³. MS is an essential tool for this purpose, as it can provide sensitive and accurate quantification of drugs and their metabolites in various biological matrices, such as plasma, urine or tissue³. MS can also be coupled with high-performance liquid chromatography (HPLC) or other separation techniques to separate and identify different metabolites of a drug³.
MS can also help to elucidate the metabolic pathways and mechanisms of a drug, as well as identify potential drug–drug interactions or adverse effects³. For example, MS can be used to analyze the enzymes that are involved in the biotransformation of a drug, such as cytochrome P450s (CYPs), by using inhibitors or substrates that are specific for each CYP isoform³. MS can also be used to detect reactive metabolites that may cause toxicity or immunogenicity by covalently modifying cellular macromolecules³.
Drug efficacy and safety
The final stage of drug development is to assess the efficacy and safety of a drug candidate in preclinical and clinical trials. MS can play a vital role in this stage by providing biomarkers that can indicate the pharmacodynamic (PD) effects of a drug, such as target engagement, pathway modulation or disease progression¹. MS can also provide biomarkers that can predict or monitor the adverse effects of a drug, such as organ toxicity or immunogenicity¹.
MS-based proteomics is one of the main approaches for biomarker discovery and validation, as it can measure changes in protein expression, modification or interaction in response to drug treatment or disease state¹. MS-based metabolomics is another complementary approach that can measure changes in metabolite levels or profiles that reflect the metabolic status or response of an organism to a drug or a disease¹. MS-based imaging is a novel technique that can provide spatial information on the distribution and localization of drugs, metabolites or biomarkers in tissues or organs¹.
Conclusion
MS is a versatile and powerful technique that can provide valuable information and insights throughout the drug discovery and development process. MS can help to identify and validate novel targets, optimize lead compounds, evaluate PK and PD properties, and monitor efficacy and safety of drug candidates. MS can also enable the development of personalized medicine by providing biomarkers that can stratify patients, predict responses or guide dosing. With the continuous advancement of MS technology and data analysis, MS will remain an indispensable tool for drug discovery and development in the future.
# References
¹: Advances in high‐throughput mass spectrometry in drug discovery | EMBO Molecular Medicine
²: The emerging role of mass spectrometry-based proteomics in drug discovery | Nature Reviews Drug Discovery
³: Mass Spectrometry for Drug Discovery and Drug Development | Wiley Online Books
Source: Conversation with Bing, 09/06/2023
(1) The emerging role of mass spectrometry-based proteomics in drug discovery. https://www.nature.com/articles/s41573-022-00409-3.
(2) Mass Spectrometry for Drug Discovery and Drug Development | Wiley .... https://onlinelibrary.wiley.com/doi/book/10.1002/9781118516157.
(3) Mass Spectrometry in Drug Discovery and Development. https://www.ddw-online.com/mass-spectrometry-in-drug-discovery-and-development-1590-201010/.
(4) Advances in high‐throughput mass spectrometry in drug discovery | EMBO .... https://www.embopress.org/doi/full/10.15252/emmm.202114850.