Medicinal Chemistry Services for DNA-Encoded Library Screening
Introduction
In modern drug discovery, medicinal chemists have more data, more biological targets, and more modalities than ever before. Yet the path from primary screening to validated chemical hits remains a bottleneck for many R&D programs. High-throughput screening, fragment campaigns and DNA Encoded Libraries (DELs) can generate long lists of potential binders, but transforming those signals into experimentally confirmed hits – quickly, reproducible, and with a clear structure activity relationship – demands specialized expertise.
Vipergen was founded to provide exactly that service as a medicinal chemistry company whose platform is built around the synthesis and screening of DELs. We focus on the initial part of the drug discovery pipeline (figure 1) and can take your target protein of interest (POI) to early lead like compounds in a few months. Hereby Vipergen’s medicinal chemistry platform can help to deliver the greatest impact and the highest return of investment. By concentrating our resources on DEL construction, selections, data analysis, and hit re-synthesis, we offer a streamlined medicinal chemistry service that plugs directly into your discovery engine – no matter whether your downstream chemistry is handled in-house or by another medicinal chemistry CRO.
Figure 1: Overview of the drug discovery and development process and indication of which steps Vipergens DEL Screening can assist your process.
Throughout this article we will explain how Vipergen’s focused medicinal chemistry solutions accelerate early drug discovery while maintaining full traceability, uncompromising quality, and competitive turnaround times. We deliver high-quality DEL hits which can readily be resynthesized off-DNA ready for the next phase.
Why utilizing DEL screening as part of medicinal chemistry campaign?
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- It Expands Chemical Space Exploration: Where commercial screening decks cover up to one million compounds, a well-designed DEL explores hundreds of millions of small molecules. This jump of almost three-fold in magnitude uncovers novel scaffolds and binding modes which traditional small-molecule screening libraries rarely touch. Vipergen’s DELs introduces thousands of designer building blocks allowing for full exploration of chemical space. Our team works daily to expand the chemical space our DNA encoded libraries explores.
- It Demands Precise Synthesis: Building a high-quality multi-million-member DEL is impossible without high-fidelity chemistry. At Vipergen we utilize our proprietary YoctoReactor technology to construct DELs with a complete match between DNA barcode and the displayed small molecule.
- It Requires Bioinformatics as Much as Bench Work: DEL selection data arrives as sequencing files, not IC50-values. Turning barcode counts into a ranked list of real molecules calls for dedicated informatics pipelines, sophisticated enrichment algorithms, and chemist who can understand both the statistics and the synthetic feasibility behind each hit. Coupling wet-lab and dry-lab expertise in one team minimizes hands-offs and maximizes interpretability.
- It gives access to maximum diversity: Vipergen’s DELs are optimized to maximize 3D diversity by introducing building blocks which display different spatial orientations. This is done by introducing chemical building blocks with distinct cores to deliver 3D diversity. To further enhance 3D diversity these cores are diversified by their stereo- and positional-isomers.
- It Gives Access to Early Structure Activity Relationship: Vipergen’s DELs includes core scaffolds decorated with diverse sets of substituents. This means that once a hit is identified, structure activity relationship (SAR) information is readily available from the DEL screen.
- It Expands Chemical Space Exploration: Where commercial screening decks cover up to one million compounds, a well-designed DEL explores hundreds of millions of small molecules. This jump of almost three-fold in magnitude uncovers novel scaffolds and binding modes which traditional small-molecule screening libraries rarely touch. Vipergen’s DELs introduces thousands of designer building blocks allowing for full exploration of chemical space. Our team works daily to expand the chemical space our DNA encoded libraries explores.
DNA-Encoded Library Platform in Detail
Library Architecture
- Scaffold-Centric Diversity: Each library member contains three-dimensional and sp3-rich core scaffolds chosen for synthetic tractability and physicochemical balance (Average for Vipergen’s Lib56: Fsp3 = 0.6; cLogP = 0.75; HBA/HBD within Lipinski limits; 343 different core-scaffolds).
- Orthogonal Encoding Tags: Our YoctoReactor technology ensures complete eliminations of truncates, ensuring every compound is uniquely addressable.
Selection Workflow
- Screening in Living Cells: Our unique screening technique inside living cells allows for rapid screening against most target classes including membrane targets as purified protein is not needed. Read more about cellular Binder Trap Enrichment here.
- Screening in vitro: Besides screening in cells, we also perform more traditional DEL screenings in vitro. Here we utilize our Binder Trap Enrichment, which omits the need for target immobilization.
- Positive and Negative Selection Rounds: We can directly screen both against target protein, but also counter-screen against non-targets which you want selectivity against.
- Screening Beyond Inhibitors: We have developed multiplex screening technologies, which allow for the direct identification of both molecular glues and protein-protein interaction inhibitors. Check out our full list of services here.
Analysis Workflow
- Next-Generation Sequencing (NGS) and Analysis: We analyze NGS data and compile a hit list and report. This includes metrics from the screen and chemical structure information.
- Hit reservation and Chemical Series Nomination: Hits are reserved for our clients for 1 year, where you may resynthesize and test in relevant assays. In this time, you may nominate chemical series, which becomes exclusive for you.
Hit Resynthesis: Converting Sequences into Samples
Engagement Models that Respect Your Pipeline
Our DEL screening services can be scaled based on your needs. We can e.g. dimension our medicinal chemistry services to:
- Easy and fast DEL screening in cells, where we initially perform an expression study, which is followed by one round of screening.
- Direct selectivity screens, where we expand the screening against anti-target protein(s).
- Multiplex screening to identify molecular glues and protein-protein interaction inhibitors.
Check out the full series of services here and contact us about your project.