Interrogating dense ligand chemical space with a forward-synthetic library

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Forward-synthetic databases offer a method for exploring vast chemical space.
• Identifying novel protein ligands, especially for well-studied targets like the beta-2 adrenergic receptor, presents a significant challenge.
• Assessing the novelty and synthetic accessibility of compounds within these databases is crucial for drug discovery.

Purpose of the Study:

• To evaluate forward-synthetic databases as a source for novel protein ligands.
• To determine the number of obtainable molecules and the timeframe for synthesis.
• To explore ligand structure-activity relationships and discover novel, dissimilar ligands for the beta-2 adrenergic receptor.

Main Methods:

• Utilizing docking calculations to select candidate molecules from forward-synthetic databases.
• Synthesizing selected molecules to experimentally validate computational predictions.
• Performing structure-activity relationship (SAR) studies on synthesized compounds.
• Assessing ligand novelty by comparison with existing known ligands for the target receptor.

Main Results:

• Successful synthesis of 127 out of 240 designed molecules within a two-week period.
• Discovery of previously unreported, dissimilar ligands for the beta-2 adrenergic receptor.
• Optimization of one ligand series to achieve a K of 519 nM in a single optimization round.
• Analysis revealed that only 3 out of 240 molecules had been previously synthesized, highlighting unexplored chemical space.

Conclusions:

• Forward-synthetic databases are a viable and efficient source for novel protein ligand discovery.
• Rapid synthesis and optimization are achievable using this approach, accelerating drug discovery timelines.
• A vast portion of chemical space remains unexplored, offering significant opportunities for identifying new therapeutic agents.