Structure and reaction based evaluation of synthetic accessibility.

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• De novo design systems generate novel molecular structures with high binding affinity.
• A key limitation is the poor synthetic accessibility of some designed molecules.
• Efficient drug discovery requires evaluating synthetic feasibility early in the design process.

Purpose of the Study:

• To develop a rapid scoring method for evaluating the synthetic accessibility of novel chemical structures.
• To address the deficiency of difficult-to-synthesize molecules in de novo design outputs.

Main Methods:

• A scoring method was devised to rapidly evaluate synthetic accessibility.
• The method considers structural complexity, starting material similarity, and strategic bond decomposition.
• Weights for scoring components were determined using linear regression against medicinal chemist assessments.

Main Results:

• The developed scoring method provides rapid synthetic accessibility evaluations.
• The method's performance correlates well with expert medicinal chemists' judgments.
• Calculated synthetic accessibility scores show good agreement with human expert evaluations.

Conclusions:

• The new scoring method effectively predicts synthetic accessibility for de novo designed molecules.
• This tool can help prioritize drug candidates with better synthesis feasibility.
• Integrating this method enhances the practicality of computational drug design.