Nanoscale synthesis and affinity ranking.

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Drug development requires optimizing compound affinity for therapeutic targets from vast chemical spaces.
• Current high-throughput synthesis methods coupled with bioassays have limitations, such as low-density arrays or material requirements.
• Existing high-density synthesis methods restrict the use of crucial transition-metal catalysts and high-concentration reactions.

Purpose of the Study:

• To develop a method merging high-throughput nanomole-scale synthesis with label-free affinity-selection mass spectrometry bioassays.
• To enable rapid exploration of chemical space for drug discovery and chemical probe development.
• To overcome limitations of existing methods regarding catalyst compatibility and reaction conditions.

Main Methods:

• Coupling high-throughput nanomole-scale synthesis with affinity-selection mass spectrometry (MS) bioassay.
• Performing reactions at 0.1 M concentration in discrete wells to facilitate transition-metal catalysis.
• Utilizing a label-free MS bioassay to rank product affinity to target proteins without purification.

Main Results:

• Enabled transition-metal catalysis and high reactant concentrations in high-throughput synthesis.
• Reduced substrate consumption to less than 0.05 mg per reaction.
• Successfully ranked the affinity of synthesized compounds to target proteins using MS bioassay.

Conclusions:

• The developed method significantly accelerates the primary synthesis and testing steps in drug invention.
• It allows for rapid identification of protein inhibitors with minimal starting material consumption.
• This approach streamlines the drug discovery process by combining efficient synthesis and direct bioassaying.