Automated Parallel Synthesis Accelerates Virtual Screening Hit Discovery.

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Virtual screening (VS) identifies potential drug candidates but suffers from low hit rates, necessitating costly experimental validation and optimization.
• The exploration of vast chemical spaces for drug discovery is limited by the time and resources required for synthesis and testing.

Purpose of the Study:

• To develop COMBINAUT, an automated parallel synthesis platform to accelerate hit validation and refinement in drug discovery.
• To demonstrate the synergy between automated synthesis and VS for efficient chemical space exploration and novel ligand discovery.

Main Methods:

• Developed COMBINAUT, an automated platform for parallel synthesis of diverse chemical scaffolds using in-house building blocks.
• Generated over 22.9 million compounds designed for parallel synthesis within 32 hours using repurposed solid-phase peptide synthesis equipment.
• Performed large-scale VS targeting the C-C chemokine receptor 2 (CCR2) allosteric pocket and synthesized/tested 100 VS hits.

Main Results:

• Successfully validated nine hits with distinct scaffolds, including novel CCR2 ligand chemotypes, from 100 synthesized VS hits.
• Iterative hit-to-lead optimization using the automated workflow yielded cell-active CCR2 antagonists.
• Demonstrated the platform's capability to rapidly synthesize and test diverse molecular architectures.

Conclusions:

• COMBINAUT significantly accelerates hit validation and refinement by enabling rapid generation of diverse compound libraries.
• The integration of automated synthesis with VS provides an efficient strategy for exploring chemical space and discovering novel drug ligands.
• This approach facilitates the rapid discovery of potent and novel therapeutic agents, exemplified by the identification of CCR2 antagonists.