Exploring the Future of Drug Discovery with DNA Encoded Libraries (DELs)

Introduction

The main challenges addressed by DEL technology

The technology

Advantages of using DEL technology

Off-the-Shelf DNA Encoded Library Kits

Looking for an extended DEL data to use in Artificial Intelligence/Machine Learning

INTRODUCTION

In the quest to discover novel therapeutic agents and revolutionize drug development, scientists have continually sought innovative approaches to accelerate the identification of potential drug candidates. One ground-breaking solution that has emerged in recent years is the utilization of DNA-encoded libraries (DELs). DELs stand as a versatile and potent technology foundation for uncovering small molecule binders for biologically and pharmaceutically significant protein targets.

DELs encompass groups of compounds, each linked to unique DNA markers that function as amplifiable identification codes. With the progress made in DNA-compatible chemical reactions, selection techniques, next-generation sequencing, and data interpretation, DEL technology enables the creation and examination of libraries with unparalleled dimensions.

Figure 1. DNA-encoded library and its mode of operation.

The main challenges addressed by DEL technology

Traditional methods of drug discovery are often time-consuming, costly, and inefficient. They rely on screening vast collections of chemical compounds to identify molecules with the desired therapeutic properties. This approach not only demands enormous resources but also limits the scope of the search to a finite chemical space. Additionally, the identification and optimization of lead compounds frequently involve extensive hit-to-lead optimization, further elongating the drug development timeline. Another challenge is the high cost of synthesizing and screening chemical compounds with many promising molecules often being overlooked due to budget constraints.

The technology

DNA encoded libraries offer a paradigm shift in drug discovery by leveraging the power of molecular biology and high-throughput screening. This technology consists of four key elements or features:

• DNA Tagging: Each chemical compound in the library is tagged with a unique DNA sequence, creating a barcode-like identifier for the molecule.
• Massive Library Size: DELs can contain billions to trillions of compounds, greatly expanding the chemical space that can be explored.
  
• High-Throughput Screening: By utilizing DNA tags, researchers can rapidly and simultaneously screen vast libraries to identify compounds binding to a specific target.
  
• Data-Driven Approach: The technology enables the generation of large-scale data sets, allowing for data analysis and machine learning approaches to identify potential leads.

Screen

• All compounds are in a single vial
• Each attached to a unique DNA barcode

Isolate

• Target immobilized on a bead
• Screen library all at once
• Wash away compounds that didn’t bind

Amplify & Sequence

• Isolate hits
• Amplify DNA with PCR
• Sequence DNA code

Identify

• Use code to determine structure of hit

Figure 2. DNA-encoded library main protocol stages (or steps). 

Advantages of using DEL technology

DELs provide access to an unparalleled diversity of chemical compounds, increasing the chances of discovering unique drug candidates. In addition, high-throughput screening with DNA tags significantly accelerates the drug discovery process, reducing development timelines, while enabling efficient resource utilization, therefore, making drug discovery more cost-effective. In conclusion, DEL technology opens doors to innovative target-based and phenotypic drug discovery approaches. 

Off-the-Shelf DNA Encoded Library Kits

Which DNA-encoded library is right for my research?

	DNA-Encoded Fragment Library	10 Million DNA-Encoded Library
Library Size	370,000 pairs	10 million compounds
Compound Type	Find paired fragments	Find hits composed of three fragments
Linkage Status	Develop linkers between pairs	Fragments already linked
Hit Method	Small size of fragments increases chance of finding a hit	Large size of library increases chance of finding a hit
Research Stage	More development work is required to form a compound.	Compound is farther along in development
Development Required	More flexibility in development	Less flexibility since more fully developed
Packaging	5 vials	2 vials or 5 vials
Structure Availability	Only hit structures available	All structures available with Data Sharing Agreement

Looking for extended DEL data to use in Artificial Intelligence/Machine Learning

DEL Data for 1 analysis of DNA-Encoded Library information - DELDATA

Introducing our state-of-the-art DNA Encoded Library (DEL) Enhanced Data Bundle, an innovative solution that introduces unmatched effectiveness and creativity to the realm of pharmaceutical research. DEL Data merges the capabilities of DNA labelling with sophisticated analysis of successful hits, enabling scientists to expedite their drug development endeavours and unveil novel therapeutic prospects. This DNA labelling method enables simultaneous screening of countless, even astronomical amounts of compounds, vastly boosting the speed and effectiveness of the screening process. The Enhanced Data Bundle elevates this technology to the next level by offering thorough and intricate insights into the hits acquired during the screening of the DNA-encoded library. It provides researchers with an exhaustive overview of the chemical structures and binding affinities of the successful compounds, giving them the authority to make informed decisions when selecting the most promising candidates for further examination.

REFERENCES

1. Reddavide FV, Cui M, Lin W, Fu N, Heiden S, Andrade H, Thompson M, Zhang Y. Second generation DNA-encoded dynamic combinatorial chemical libraries. Chem. Commun.. 55(26):3753-3756. https://doi.org/10.1039/c9cc01429b

2. Jhoti H, Williams G, Rees DC, Murray CW. 2013. The 'rule of three' for fragment-based drug discovery: where are we now?. Nat Rev Drug Discov. 12(8):644-644. https://doi.org/10.1038/nrd3926-c1

3. Murray CW, Rees DC. 2009. The rise of fragment-based drug discovery. Nature Chem. 1(3):187-192. https://doi.org/10.1038/nchem.217

4. Satz AL. 2018. What Do You Get from DNA-Encoded Libraries?. ACS Med. Chem. Lett.. 9(5):408-410. https://doi.org/10.1021/acsmedchemlett.8b00128

5. Reddavide FV, Lin W, Lehnert S, Zhang Y. 2015. DNA‐Encoded Dynamic Combinatorial Chemical Libraries. Angew Chem Int Ed. 54(27):7924-7928. https://doi.org/10.1002/anie.201501775