Overview of Hit and Analogue

Hit and analogue synthesis are key processes in drug discovery and development. Once the initial "hit" of the desired biological activity is identified, the subsequent synthesis of these compounds and their analogues achieve structural changes that enhance potency, selectivity, and pharmacokinetic properties. By creating a series of analogues, researchers characterize their structure-activity relationships (SARs) to understand how different functional groups and molecular frameworks affect the biological activity and efficacy of the compound. This iterative process helps refine the hit into a lead compound by improving its drug-like properties, reducing potential off-target effects, and increasing the likelihood of success in clinical development. In addition, this detailed analysis helps understand the mechanism of action and potential side effects, ultimately leading to the creation of safer and more effective drugs.

Precise Hit and Analogue Synthesis for Drug Development

At CD BioGlyco, we have developed a one-stop solution (such as Library Construction, Screening, Data Analysis, etc.) for applying DNA-encoded library (DEL) technology to glycan-based research and drug development. Hit and analogue synthesis is an important part of the process. Our service process is as follows:

Design and Screening of DEGL

DEGL combines the high-throughput capabilities of DEL technology with the structural diversity of glycans to create a powerful system for identifying bioactive compounds. We use DEGL technology to bind a large number of glycans to DNA, and each glycan unit carries a unique DNA barcode as an identifier. The constructed DEGL is then screened against a target (such as a protein, enzyme, or cell receptor), allowing thousands to millions of glycan structures to be evaluated simultaneously in a single experiment to screen for potential hits. The DNA barcode is sequenced to decode the binding interaction between the glycan and the target.

Hit and Analogue Synthesis

Hit and analogue synthesis is an efficient method to identify and optimize bioactive molecules that interact with specific targets. We start with identifying hit compounds from DEGL screening, identify promising hit compounds, and proceed with the synthesis of hits and their analogues to elucidate SAR. This process includes the identification, synthesis, and evaluation of analogues using advanced methods in medicinal chemistry, molecular biology, and analytical techniques. At CD BioGlyco, our commonly used strategies for hit and analogue synthesis are as follows:

• On-DNA Hit and Analogue Synthesis: After the high-throughput screening of DEGL and the sequencing and decoding of the screening results, some of the most enriched building blocks used in each round of the library construction process will be obtained. We take these building blocks and synthesize this compound using the same chemical reaction conditions that were used to construct the library. The difference is that the construction of DEGL is to combine a large number of building blocks with different DNA sequences to obtain DEGL containing different compounds. For the synthesis of on-DNA hit and analogue, we only need one of building block to synthesize the unique product.
• Off-DNA Hit and Analogue Synthesis: Off-DNA hit and analogue synthesis is the synthesis of small molecules outside of a DEL system. This approach allows for a wider range of chemical reactions and optimization steps due to the absence of limitations associated with DNA stability. We start with the bulk chemical synthesis of hit compounds and make systematic modifications to generate a series of analogues. These analogues are then subjected to a variety of analyses to evaluate their biological activity and other properties.

Workflow

Applications

• Lead compound synthesis and optimization: Chemical modifications are made to the hit to improve its pharmacological properties, such as potency, selectivity, and bioavailability. SAR studies are used to improve the chemical structure to increase activity and reduce potential side effects.
• Target validation: Analogues with different degrees of activity are synthesized and observed to see how they interact with the target, gaining insight into the molecular mechanisms involved and confirming the relevance of the target in the disease pathway.
• Drug resistance studies: In fields such as antibiotic or antiviral research, synthetic analogues are used to identify compounds that overcome resistance mechanisms. By understanding how modifications affect activity, researchers design drugs that are effective against resistant strains.

Advantages

• We provide a range of services from rapid initial compound screening to hit synthesis, bioactivity assays, and SAR studies. The complete process helps you accelerate the process from target discovery to drug discovery, reducing the time and cost associated with the traditional drug discovery process.
• The synthesis of hits and analogues utilizes high-throughput synthesis technology and advanced analytical tools to reduce time and labor costs while ensuring high purity and accurate characterization of synthetic compounds.
• Customized hit synthesis services are performed based on the specific needs of the project, providing solutions that meet the unique requirements of each research plan. This flexibility allows for the incorporation of iterative feedback and continuous improvement of compound libraries.

Publication Data

Frequently Asked Questions

• How are hits and their analogue validated?
  • The hit compounds in DEGL and their analogues are validated through a multi-step process, starting with a primary screening to identify potential hit compounds that exhibit the desired biological activity. These compounds are then synthesized to confirm that the observed activity is caused by the compound itself and is not affected by DNA. The synthesized compounds are then subjected to secondary analysis to confirm their activity, specificity, and potency. Further validation involves SAR studies to understand the effects of various chemical modifications on their activity.
• How do we assess the quality of hit compounds?
  • We identify hit compounds through HTS and use a combination of biochemical and biophysical analyses to validate their qualities, such as binding affinity, specificity, and stability. Techniques such as surface plasmon resonance (SPR) are used to measure binding kinetics and thermodynamic parameters. Structural analysis methods such as X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy are used to confirm the interaction mode between the compound and the target molecule. Cytotoxicity assays and cell-based models are combined to assess biological relevance and potential off-target effects.

At CD BioGlyco, our comprehensive hit service process assists your early drug development, helping you quickly screen hits, verify biological activity, and study SAR. If you have hit and analogue synthesis needs, please feel free to contact us, our experts will customize professional solutions for you according to your needs.

• Hit Activity Verification
• Structure-Activity Relationship (SAR) Optimization of Hits