The Logic of Chemical Optimization.

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• Molecular capabilities advance during drug optimization, evolving hits into leads and candidates.
• Retrosynthetic analysis simplifies target molecules into starting materials.
• Understanding past optimization logic is crucial for future drug discovery.

Purpose of the Study:

• Introduce retro-optimization analysis to understand chemical optimization logic.
• Compare actual optimization routes with theoretical alternatives.
• Identify and track key substructures driving optimization, termed "optimizons".

Main Methods:

• Developed retro-optimization analysis by reversing the optimization process.
• Constructed a matched molecular pair network for analysis.
• Applied the method to multiple discovery projects and external datasets.

Main Results:

• Identified differences between actual and theoretical optimization pathways.
• Characterized the properties of lead molecules in relation to alternatives.
• Demonstrated consistent findings across diverse datasets.

Conclusions:

• Retrospectively defined optimization logic at project, molecular, and submolecular levels.
• Established a novel method for analyzing and guiding drug optimization.
• Provided insights for prospective optimization campaigns in drug discovery.