Analysis of Current DNA Encoded Library Screening Data Indicates Higher False Negative Rates for Numerically Larger Libraries

To optimize future
DNA-encoded library design, we have attempted
to quantify the library size at which the signal becomes undetectable.
To accomplish this we (i) have calculated that percent yields of individual
library members following a screen range from 0.002 to 1%, (ii) extrapolated
that ∼1 million copies per library member are required at the
outset of a screen, and (iii) from this extrapolation predict that
false negative rates will begin to outweigh the benefit of increased
diversity at library sizes >108. The above analysis
is
based upon a large internal data set comprising multiple screens,
targets, and libraries; we also augmented our internal data with all
currently available literature data. In theory, high false negative
rates may be overcome by employing larger amounts of library; however,
we argue that using more than currently reported amounts of library
(≫10 nmoles) is impractical. The above conclusions may be generally
applicable to other DNA encoded library platforms, particularly those
platforms that do not allow for library amplification.