DNA encoded libraries connect small molecules with genetic information and became an important tool for drug discovery in both academia and industry [1]. They allow the construction of libraries with millions of different members that can be tested at the same time using, for example, affinity enrichments. A major disadvantage is the limited number of chemical transformations available that reduce the available chemical space [2], although there has been some significant progress on that in the recent years [3].

A key problem of reactions in DNA encoded reactions is always the side reactions they might undergo with the DNA tag, impairing the genetic information. A popular approach is the measurement of DNA amplifiability by utilizing qPCR [4]. More recently, characterization of reaction conditions according to their encoding fidelity has been shown [5]. Herein, we give insight into a third parameter that can be used to characterize reactions. Modifications of nucleobases can cause mutations and, as a result, the DNA used for encoding can change.

[1] Lik Hang Yuen, Raphael M. Franzini, ChemBioChem, 2017, 18, 9, 829–836.
[2] Raphael M. Franzini, Cassie Randolph, J. Med. Chem., 2016, 49, 14, 6629–6644.
[3] (a) Alexander Lee Satz, Jianping Cai, Yi Chen, Robert Goodnow, Felix Gruber, Agnieszka Kowalczyk, Ann Petersen, Goli Naderi-Oboodi, Lucja Orzechowski, Quentin Strebel, Bioconjugate Chem. 2015, 26, 8, 1623–1632. (b) Dillon T. Flood, Shota Asai, Xuejing Zhang, Jie Wang, Leonard Yoon, Zoë C. Adams, Blythe C. Dillingham, Brittany B. Sanchez, Julien C. Vantourout, Mark E. Flanagan, David W. Piotrowski, Paul Richardson, Samantha A. Green, Ryan A. Shenvi, Jason S. Chen, Phil S. Baran, Philip E. Dawson, J. Am. Chem. Soc. 2019, 141, 25, 9998–10006.
[4] (a) Marie L. Malone, Brian M. Paegel, ACS Comb. Sci., 2016, 18, 4, 182–187. (b) Cedric J. Stress, Basilius Sauter, Lukas A. Schneider, Timothy Sharpe, Dennis Gillingham, Angew. Chem. Int. Ed., 2019, 58, 28, 9570–9574.
[5] Anokha S. Ratnayake, Mark E. Flanagan, Timothy L. Foley, Justin D. Smith, Jillian G. Johnson, Justin Bellenger, Justin I. Montgomery, Brian M. Paegel, ACS Comb. Sci., 2019, 21, 10, 650–655.