HitGen-DNA Encoded Library-Drug Discovery

DNA Encoded Library Synthesis

Select diverse and novel chemical structures as scaffolds
Link Building Blocks with scaffolds and repeat the practice of “Split&Pool”
After a round of linking building block, encode each compound with a given sequence of DNA
Produce a DNA Encoded Library of millions and billions of compounds

DNA-encoded libraries are hybrid-type libraries that bring together beneficial aspects from conventional combinatorial libraries and display technologies, such as phage display. The practice of “Split & Pool” strategy enables production of huge collections of molecules. Furthermore, every compound in the libraries is encoded with a given sequence of DNA on molecular level. By using diverse actives as scaffolds, HitGen can achieve the chemical diversity and novelty of DELs.

DNA Encoded Library Screening

Screen DELs of vast number of compounds simultaneously against a target
Sequence encoded tags (DNA) of the selected hits compounds and obtain their chemical information
Hits identification and optimize the chemical structures
Generate Hits and optmization

Incubate the active immobilized target protein and DNA encoded library for some time; during the time, compounds with strong affinity will bind to the protein while non-binders / weak-binders will be eluted. Denature the protein with heat and elute the selected binders. Elucidate the structure of binders through PCR amplification / DNA sequencing. Re-synthesize off-DNA for confirmation of activity. Optimize chemical structure to generate lead compounds.

The Quality of DNA Encoded Library

1Chemical Diversity
Over 800 DELs are synthesized, with 40% Target relevant, 25% Macrocycles, 9% Peptidomimetics, 1% Natural products and other DELs. Target relevant DELs are mainly focused on challenging targets such as PPI which are difficult to screen by using traditional libraries.

2Structure Novelty
The side-by-side comparison between 1 million molecules from ZINC & ChemBL and 0.1 billion small molecules that are randomly selected from HitGen small molecular libraries indicate that tanimoto similarity is below 0.3.

3Drug-like Libraries
Visual representation of different chemical collections in physicochemical descriptors [ALogP, MW, HBD, HBA, RB, NR, NAR, PSA, …] and molecular fingerprint [ECFP4] space followed by principle component analysis (PCA). 1M HitGen small molecules are randomly selected from HitGen small molecular libraries. Approved and experimental drugs are downloaded from Drugbank. [MW≤650 Da].

4Advantages
Instead of merely pursuing large-size libraries, HitGen has been selecting drug-like and novel chemical structures as scaffolds to build mid-size libraries, which assured the diversity and novelty of the compounds. Moreover, comparing to traditional HTS library, DNA encoded library contains more compounds, which are much easier to screen against challenging targets.

Technology

DNA Encoded Library Synthesis

DNA Encoded Library Screening

The Quality of DNA Encoded Library