Combining High-Throughput Synthesis and High-Throughput Protein Crystallography for Accelerated Hit Identification

Area of Science:

• Structural biology
• Medicinal chemistry
• Drug discovery

Background:

• Protein crystallography (PX) is crucial for drug optimization and fragment-based drug discovery.
• Advancements in PX offer potential for earlier integration into the drug discovery pipeline.

Purpose of the Study:

• To demonstrate the synergy between high-throughput synthesis and high-throughput protein crystallography (HTPX).
• To develop a rapid method for generating and screening covalent inhibitor libraries.

Main Methods:

• A multicomponent reaction strategy for synthesizing acrylamides and esters in 96-well and nanoscale formats.
• Automated, high-throughput synthesis and HTPX screening of compound libraries.
• Covalent inhibitor identification targeting the SARS-CoV-2 main protease.

Main Results:

• Successfully synthesized diverse compound libraries using a high-throughput, automated approach.
• HTPX screening efficiently identified potent covalent inhibitors of the SARS-CoV-2 main protease.
• Demonstrated the feasibility of integrating in situ library synthesis with HTPX.

Conclusions:

• The combination of in situ high-throughput synthesis and HTPX significantly accelerates hit identification.
• This integrated strategy provides a powerful approach for medicinal chemistry projects.
• Enables rapid development of covalent inhibitors for viral targets like SARS-CoV-2.