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Publication Abstract from PubMed

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 and partially automated design of potent chemical probes consisting of 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 that are 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 affinity improved by several orders of magnitude.

An Integrated Strategy for Lead Optimization based on Fragment Growing: The DOTS (Diversity-Oriented Target-focused Synthesis) Approach.,Hoffer L, Voitovich YV, Raux B, Carrasco K, Muller C, Fedorov AY, Derviaux C, Amouric A, Betzi S, Horvath D, Varnek A, Collette Y, Combes S, Roche P, Morelli X J Med Chem. 2018 Jun 8. doi: 10.1021/acs.jmedchem.8b00653. PMID:29883107^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.