How Do Natural Products Identify Their Targets? Chemical Proteomics Provides the Answer
Natural products have long served as a vital reservoir for drug discovery, with over 50% of approved clinical drugs being either directly derived from or structurally modified based on them. However, their structural complexity and often elusive mechanisms of action have posed significant barriers to drug development. Particularly during early-stage screening, the absence of known molecular targets represents a major challenge to elucidating pharmacological mechanisms and guiding subsequent structural optimization. By what mechanisms do natural products exert their effects within cells? Which proteins do they interact with? These questions lie at the core of what chemical proteomics is particularly well-equipped to address.
What Is Chemical Proteomics? A Strategy Linking Small Molecules to Target Proteins
Chemical proteomics is an interdisciplinary approach that integrates chemical synthesis, proteomics, and systems biology with the primary aim of systematically characterizing interactions between small molecules and proteins within complex biological environments. Unlike the traditional “target-first” paradigm in drug development, chemical proteomics is often employed in a “target deconvolution” context, where small molecules serve as probes to retrospectively identify their cellular binding partners. This approach is especially advantageous for studying natural products. Due to their inherent structural complexity and novelty, many natural products are not amenable to classical reverse pharmacology strategies. Chemical proteomics thus offers a more physiologically relevant and systematic route for target identification in these cases.
Chemical Proteomics Strategies Commonly Employed for Target Identification of Natural Products
1. Activity-Based Probes (ABPs)
This strategy involves minimally modifying the natural product to introduce a photoreactive group or an affinity tag (such as biotin). Upon binding to target proteins, the probe-protein complexes can be stabilized through ultraviolet-induced cross-linking or affinity-based purification. The labeled proteins are then identified using mass spectrometry. This method offers high specificity and is particularly suitable for natural products that target enzyme classes.
2. Affinity-Based Protein Profiling (AfBP)
In the AfBP approach, natural products are covalently or non-covalently immobilized onto solid-phase supports (e.g., magnetic beads) and incubated with cellular lysates to allow interaction with protein targets. Following washing and elution steps, the bound proteins are identified using high-resolution mass spectrometry. This method is less dependent on protein abundance and is effective for detecting low-affinity interactions, making it broadly applicable in natural product research.
3. Thermal Shift Profiling
This technique exploits the principle that the binding of small molecules alters the thermal stability of their target proteins. Cells or lysates are exposed to a temperature gradient, and quantitative proteomic analysis is used to identify proteins exhibiting significant thermal stability shifts. As this method does not require chemical modification of the natural product, it is particularly suitable for compounds that are structurally challenging to derivatize.
Why Choose Chemical Proteomics?
1. High in Situ Fidelity Reflecting Physiological Conditions
Chemical proteomics is typically conducted at the cellular or tissue level, enabling the investigation of natural products in a biologically relevant context. This approach minimizes the discrepancies often introduced by in vitro experiments, thereby preserving the native mechanism of action of natural compounds.
2. Well-Suited to the Structural Diversity of Natural Products
Unlike traditional rational drug design strategies, chemical proteomics does not rely on prior knowledge of target proteins. This makes it particularly compatible with natural products, which are often characterized by structurally complex and non-canonical frameworks.
3. Data Traceability Supporting Mechanistic Insights
When coupled with high-resolution mass spectrometry, chemical proteomics enables precise identification of protein targets. Furthermore, the resulting data can be leveraged to support downstream studies such as mechanism-of-action elucidation, signaling pathway analysis, and functional validation.
Serving as a critical interface between small molecules and proteins, chemical proteomics is emerging as a powerful tool in the pharmacological investigation of natural products. MtoZ Biolabs offers a comprehensive chemical proteomics workflow that spans experimental design, sample preparation, probe synthesis, target identification, and data analysis. This end-to-end solution is designed to support a wide range of research needs in drug discovery and development, including biomarker identification, drug-target interaction mapping, pathway modeling, and mechanistic studies.
MtoZ Biolabs, an integrated chromatography and mass spectrometry (MS) services provider.
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