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

• Published in: Journal of medicinal chemistry Vol. 61; no. 13; pp. 5719 - 5732
• Main Authors: Hoffer, Laurent, Voitovich, Yuliia V, Raux, Brigitt, Carrasco, Kendall, Muller, Christophe, Fedorov, Aleksey Y, Derviaux, Carine, Amouric, Agnès, Betzi, Stéphane, Horvath, Dragos, Varnek, Alexandre, Collette, Yves, Combes, Sébastien, Roche, Philippe, Morelli, Xavier
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-07-2018
• Subjects: Chemical Sciences; Cheminformatics; Chemistry Techniques, Synthetic; Drug Discovery - methods; Medicinal Chemistry; Reproducibility of Results; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Time Factors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00653

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.