Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach

Over
the past few decades, hit identification has been greatly
facilitated by advances in high-throughput and fragment-based screenings.
One major hurdle remaining in drug discovery is process automation
of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient
integrated strategy for H2L optimization as well as a partially automated
design of potent chemical probes consisting of a focused-chemical-library
design and virtual screening coupled with robotic diversity-oriented
de novo synthesis and automated in vitro evaluation. The virtual library
is generated by combining an activated fragment, corresponding to
the substructure binding to the target, with a collection of functionalized
building blocks using in silico encoded chemical reactions carefully
chosen from a list of one-step organic transformations relevant in
medicinal chemistry. The proof of concept was demonstrated using the
optimization of bromodomain inhibitors as a test case, leading to
the validation of several compounds with improved affinity by several
orders of magnitude.