Designing DNA Encoded Libraries of Diverse Products in a Focused Property Space

DNA encoded libraries (DEL) are being used as a complement
or alternative
to traditional high throughput screening (HTS). To maximize the chances
of finding chemically attractive lead material that is appropriate
for medicinal chemistry optimization, for example, in the Rule of
Five compliant chemistry space, it is important to design DEL library
compounds such that they are highly diverse and fall within a desired
property space. Currently available library design methods can be
classified as either monomer-based or product-based. As monomers may
undergo significant structural changes when participating in a reaction,
monomer based design can provide a poor representation of the properties
of resultant DEL products. However, product-based design introduces
a technical obstacle due to the enormous chemical design space for
many DELs. Here a new method for monomer based selections is described
using representative sublibraries as surrogates for fully enumerated
DEL property-based optimization. Through a series of rational and
systematic library enumerations and property calculations, building-block
representatives are identified and representative sublibraries are
defined to drive the optimization process. A published data set for
a triazine library was used to demonstrate the effectiveness of the
multiple objective optimization for six properties. All of the evaluated
properties for the designed library are shown to consistently shift
toward the desired property distribution as driven by the design criteria.