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Analysis of Current DNA Encoded Library Screening Data Indicates Higher False Negative Rates for Numerically Larger
Alexander L Satz1, Remo Hochstrasser1, Ann C Petersen1
1Roche Pharmaceutical Research and Early Development (pRED) Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd. , Grenzacherstrasse 124 CH-4070 Basel, Switzerland.
ACS Combinatorial Science
|March 14, 2017
Summary
Optimizing DNA-encoded library design requires understanding limits. Exceeding 10^8 library members increases false negatives, diminishing the benefits of diversity in screening.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Molecular Biology
Background:
- DNA-encoded libraries (DELs) are powerful tools for drug discovery.
- Optimizing DEL design is crucial for efficient screening.
- Quantifying library size limits is essential for future DEL development.
Purpose of the Study:
- To determine the maximum effective size of DNA-encoded libraries.
- To identify the point at which screening signals become undetectable.
- To provide guidelines for future DEL design and optimization.
Main Methods:
- Analysis of a large internal dataset from multiple screens, targets, and libraries.
- Augmentation of internal data with published literature data.
- Calculation of individual library member yields and required starting copies.
- Extrapolation to predict false negative rates at increasing library sizes.
Main Results:
- Individual library member yields in screens range from 0.002% to 1%.
- Approximately 1 million copies per library member are needed at the outset of a screen.
- False negative rates outweigh diversity benefits at library sizes greater than 10^8.
- Using >10 nmoles of library is considered impractical.
Conclusions:
- Library sizes exceeding 10^8 may lead to unacceptable false negative rates.
- The findings are applicable to various DNA-encoded library platforms, especially those without amplification.
- Practical limitations exist for overcoming high false negative rates by increasing library amounts.
