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Identification of Direct Targets for Non-covalent Small Molecule Drugs
In the field of drug development for diseases, small molecule drugs undoubtedly play a crucial role. According to recent statistics, among the 854 human protein targets targeted by FDA-approved drugs, a staggering 84% correspond to small molecule drugs. Notably, only 665 of these targets have been successfully developed with small molecule drugs (source: https://www.proteinatlas.org/humanproteome/tissue/druggable). Small molecule drugs can interact with target proteins through non-covalent and covalent mechanisms. The vast majority of interactions between small molecule drugs and target proteins occur in a non-covalent manner, forming dynamic and reversible interactions with amino acid residues in binding pockets through mechanisms such as hydrogen bonds, π-π stacking, and hydrophobic interactions. Therefore, stabilizing the enrichment and isolation of proteins bound by non-covalent small molecule drugs from complex proteomes presents a highly challenging task.
To address this challenge, Chomix has developed a chemical proteomics target identification technology platform based on photoprobes. This platform accurately captures the dynamic binding between small molecules and proteins in living cells and achieves separation and enrichment, comprehensively identifying direct targets for non-covalent small molecule drugs at the proteomic level.
Technical Platform
The chemical proteomics target identification platform based on photoprobes involves key steps like probe design, synthesis, activity assessment, labeling, protein enrichment, and data analysis. Non-covalent small molecule drugs, including synthetics, herbal compounds, naturals, and metabolites, can be modified into photoreactive probes. These probes, upon binding to targets within cells, form stable covalent interactions, enabling selective enrichment and identification of low-abundance target proteins. Combined with various experimental setups, this approach provides comprehensive quantification of target proteins, elucidates mechanisms, discovers new targets, and enhances drug development with richer insights.
Our Advantages
1. Technical Excellence: Experienced team, top-tier journal publications, and authoritative industry services.
2. Core Patent Technology: Exclusive patents and advanced hardware for early drug development support.
3. One-stop Service: Covering probe design, synthesis, target discovery, bioinformatics analysis, and timely progress feedback for customer satisfaction.
4. Rigorous Quality Management: ISO9001 certification ensures trustworthy and authentic reports.
Our Service
| Project | Identification of Direct Targets for Non-covalent Small Molecule Drugs |
| Sample | Pure protein, cell lysate, live cells, diseased tissue, blood, bacteria, plant tissue |
| Hardware Platform | Non-contact ultrasonic cell pulverizer，ChemiDoc MP Imaging System，Orbitrap Fusion Lumos Tribrid/Orbitrap Exploris 480/Q Exactive HF-X/timsTOF Pro 2 mass spectrometer |
| Project Duration | 4-8 weeks |
| Deliverables | Project Report (including experimental procedures, data analysis charts, bioinformatics analysis results) |
| Price | Click to consult |
Case Study
During the drug screening process, utilizing cell viability screening technology, compound A was found to exhibit significant inhibitory effects on target cells. To further identify its target proteins at the molecular level, decipher its mechanism of action, and explore potential new targets, our company designed and synthesized photoreactive probe Probe A (incorporating photoreactive and bioorthogonal groups) based on the structure and activity characteristics of compound A. Leveraging the chemical proteomics technology platform, we employed fluorescence labeling and mass spectrometry techniques for target protein identification in cell lines relevant to the activity. Combined with bioinformatics analysis methods, we delved deeper into the mechanism of action of compound A and its associated novel target proteins.
Based on fluorescence gel analysis of the labeling experiment, Probe A effectively labels proteins, and the labeling signal can be significantly competed by compound A. This indicates that Probe A has a similar target coverage to compound A, making it a suitable chemical probe tool for subsequent target discovery.
The Volcano plot illustrates the results of the Probe A vs DMSO (Direct) experiment, where 114 proteins (highlighted in red in the upper plot) were significantly enriched by Probe A. In the Probe A vs (A+Probe A) (Competition) experiment, 38 proteins (highlighted in red in the lower plot) were labeled by Probe A and significantly competed by the original compound A. These two experiments generated 32 proteins with high confidence binding to compound A (n = 3, ratio ≥ 2, p-value ≤ 0.05). GO Biological Pathway analysis of the 32 proteins with high confidence binding to compound A revealed significant enrichment in signaling pathways such as phospholipid efflux, negative regulation of lipase activity, and regulation of sterol transport, aligning with the phenotype.
