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J Med Chem. 2018 Jul 12;61(13):5719-5732. doi: 10.1021/acs.jmedchem.8b00653. Epub 2018 Jun 22.

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

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CRCM, CNRS, Inserm, Institut Paoli-Calmettes , Aix-Marseille University , 13009 Marseille , France.
Department of Organic Chemistry , Lobachevsky State University of Nizhni Novgorod , 23 Gagarin Avenue , 603950 Nizhni Novgorod , Russia.
IPC Drug Discovery Platform , Institut Paoli-Calmettes , 232 Boulevard de Sainte-Marguerite , 13009 Marseille , France.
Laboratoire de Chemoinformatique, CNRS UMR7140 , 1 rue Blaise Pascal , 67000 Strasbourg , France.


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.

[Indexed for MEDLINE]

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