DNA-encoded libraries (DELs) screening is an advanced technique that has revolutionized the field of small-molecule drug discovery. Unlike traditional high-throughput screening methods that require testing individual compounds, DELs screening allows the simultaneous evaluation of billions to trillions of compounds in a single experiment. This innovative approach not only increases the efficiency and effectiveness of the drug discovery process but also significantly reduces costs and resource consumption. By leveraging the unique properties of DNA barcodes attached to chemical compounds, DELs screening provides a robust platform for identifying high-affinity binders and potential therapeutic agents.
DELs Selection Principles and Strategies
High Target Concentration and Low Compound Concentration
DELs selection employs high concentrations of target proteins (in the micromolar range) to drive the equilibrium toward the formation of target-compound complexes. This strategy ensures that even low-affinity interactions can be detected, enabling the identification of a broader range of potential hits. The use of high target concentrations also means that lower concentrations of individual compounds (as low as 10^5 molecules per compound) are needed, making it feasible to screen vast libraries in a single experiment.
Functional Hit Identification
DELs screening goes beyond merely identifying binders by distinguishing compounds based on their functional activity. This approach involves using multiple samples and varying conditions to identify compounds that exhibit the desired biological effects. For example, competition assays with known binders can reveal information about binding sites, while the addition of substrates that induce conformational changes can provide insights into cooperative binding mechanisms. By focusing on functional hits, DELs screening ensures that the identified compounds are not only binders but also possess the desired therapeutic properties.
DELs Selection and Hit Identification Process
Pre-Selection Studies
Confirm target activity and feasibility to minimize false positives and ensure target behaves similarly to its original conditions.
General Selection Steps
Involves target-library incubation, removal of unbound molecules, and recovery of bound molecules.
Next-Generation Sequencing (NGS)
Uses NGS for high-efficiency sequencing of PCR-amplified products. qPCR monitors elution copy numbers to decide when to stop multi-round selection.
Automation and Data Processing
Employs automated systems like KingFisher for sample purification.
Key Features of DELs Screening
- Vast Chemical Space
DELs screening can access and evaluate libraries comprising billions to trillions of compounds, far exceeding the capacity of traditional screening methods.
- Efficiency and Cost-Effectiveness
The use of DNA barcoding and NGS allows for high-throughput and parallel processing of samples, making the overall process more cost-effective compared to traditional high-throughput screening techniques.
- Customizable and Flexible
DELs screening services provide customizable and flexible pooling strategies tailored to the specific needs of each project. This includes selecting the appropriate libraries, optimizing selection conditions, and ensuring high-quality target proteins.
- Advanced Validation Techniques
Affinity selection-mass spectrometry (ASMS) and various cleavable linkers ensure accurate on-DNA validation, while structure-signal relationship analysis guides further optimization of the hits. These validation steps are crucial for transitioning from hit identification to lead optimization.
DNA-encoded libraries (DELs) screening represents a paradigm shift in small-molecule drug discovery, offering unprecedented access to vast chemical spaces, enhanced efficiency, and cost-effectiveness. By leveraging high target concentrations, sophisticated data analysis, and customizable pooling strategies, DELs screening identifies functional hits with high specificity and potency. Contact us today to learn more about our services and discover how we can empower your journey towards innovation and success.