title: Analysis of Current DNA Encoded Library Screening Data Indicates Higher False Negative Rates for Numerically Larger Libraries.
abstract: 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.
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED) Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd. , Grenzacherstrasse 124 CH-4070 Basel, Switzerland.
authors.forename: Alexander L
authors.identifier: 0000-0003-1284-1977
authors.initials: AL
authors.lastname: Satz
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED) Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd. , Grenzacherstrasse 124 CH-4070 Basel, Switzerland.
authors.forename: Remo
authors.initials: R
authors.lastname: Hochstrasser
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED) Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd. , Grenzacherstrasse 124 CH-4070 Basel, Switzerland.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Petersen
mesh_terms: D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000737:chemistry*; D055808:Drug Discovery; D015394:Molecular Structure; D054852:Small Molecule Libraries
chemical_list: D054852:Small Molecule Libraries; D004247:DNA
keywords: DNA-encoded libraries; combinatorial chemistry; drug discovery; molecular diversity; screening