Identification of Binding Pockets for Non-covalent Small Molecule Drugs

In the process of small molecule drug development, understanding the binding mode between drugs and target proteins is crucial for elucidating drug mechanisms and guiding subsequent structural optimization. Structural biology techniques such as X-ray crystallography, cryo-electron microscopy (cryo-EM), and nuclear magnetic resonance (NMR) have become key tools for determining drug binding models. Particularly, high-resolution drug-protein co-crystal structures have greatly facilitated drug structure optimization.

However, protein structure elucidation, especially for membrane protein targets such as GPCRs and ion channels, has been a daunting challenge in life science research. This process involves multiple steps including protein expression and purification, screening of conditions for drug-protein crystallization, crystal data collection, and analysis, which are not only time-consuming but also costly.

At the cellular level, directly studying the mode of action between drugs and target proteins can help avoid changes in protein structure during purification and false-positive results that may arise from artificial buffer systems and high drug-protein concentrations. Chomix is committed to providing one-stop services, utilizing advanced technologies to address the challenges of determining the interaction between small molecule drugs and target proteins from cells, thereby providing strong technical support for clients' drug development efforts.

Technical Platform

Chomix provides chemical proteomics services utilizing biologically active photoreactive chemical probes (with activity similar to drug molecules). These probes are incubated with disease-relevant cells or tissues at physiologically relevant concentrations of drugs, followed by in situ rapid photo-crosslinking technology to convert non-covalent interactions between drug molecule probes and protein targets into covalent interactions. Subsequently, through steps such as target protein enrichment, enzymatic digestion to release unmodified peptide segments, and selective enrichment of drug molecule probe-modified peptide segments, combined with high-resolution mass spectrometry of biomolecules, peptide sequence information can be rapidly determined. Finally, molecular docking tools are employed to quickly obtain binding models of drugs with target proteins, providing robust support for subsequent medicinal chemistry research.


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 Binding Pockets 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  2-4 weeks
Deliverables Project Report (including experimental procedures, data analysis charts, bioinformatics analysis results)
Price Click to consult

Case Study

The target of candidate drug molecule B is a multi-transmembrane protein with multiple drug binding pockets. Despite multiple attempts using structural biology methods such as X-ray and cryo-EM, a binding model between the drug molecule and the target protein could not be obtained.
Based on the structure and activity of candidate drug molecule B, our company designed and synthesized a photoreactive chemical probe, Probe B, comprising photoreactive and bioorthogonal groups. Utilizing the chemical proteomics target discovery platform mentioned above, target proteins were first validated in cell lines relevant to the activity of candidate drug molecule B. Subsequently, leveraging mass spectrometry-based non-covalent drug binding pocket identification technology, the spatially adjacent peptide segments to the drug binding pockets were determined, and a drug-protein binding model was provided.


Immunoblotting assays revealed that candidate drug molecule B effectively competes with probe labeling signals in cells, indicating direct binding between the candidate drug molecule and the target protein.


As chemical probes can only crosslink with peptide segments in close spatial proximity, the sequence CLPFIIGCNPTILHVHELYIR was identified through tandem high-resolution mass spectrometry to determine the crosslinked peptide segments.

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