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CRISPR/Cas9-mediated Targeted Integration In Vivo Using a Homology-mediated End Joining-based Strategy
Published on: March 12, 2018
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Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis
Laurent Hoffer1, Yuliia V Voitovich1,2, Brigitt Raux1
1CRCM, CNRS, Inserm, Institut Paoli-Calmettes , Aix-Marseille University , 13009 Marseille , France.
Journal of Medicinal Chemistry
|June 9, 2018
Summary
This study introduces an automated strategy for drug discovery, streamlining hit-to-lead optimization. The novel approach accelerates the design and synthesis of potent chemical probes, improving drug development efficiency.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Chemical Biology
Background:
- High-throughput and fragment-based screening have advanced hit identification.
- Automating hit-to-lead (H2L) optimization remains a significant challenge in drug discovery.
Purpose of the Study:
- To develop a time- and cost-efficient integrated strategy for automated H2L optimization.
- To create potent chemical probes through a partially automated design process.
Main Methods:
- Focused-chemical-library design and virtual screening.
- Robotic diversity-oriented de novo synthesis.
- Automated in vitro evaluation.
- In silico generation of virtual libraries by combining fragments with building blocks using one-step organic reactions.
Main Results:
- Demonstrated a proof-of-concept using bromodomain inhibitors.
- Validated several compounds with significantly improved binding affinity (several orders of magnitude).
Conclusions:
- The integrated strategy offers an efficient approach to H2L optimization.
- This method facilitates the rapid design and synthesis of potent chemical probes for drug discovery.
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