RENATE: A Pseudo-retrosynthetic Tool for Synthetically Accessible de novo Design

Area of Science:

• Computational chemistry and drug discovery.
• Development of novel algorithms for molecular design.

Background:

• Reaction-based de novo design aims to generate synthetically accessible molecules using literature-derived reaction rules.
• Previous work involved extracting reaction vectors and coupling them with structure generation algorithms.
• A key challenge is the combinatorial explosion of possible molecules in multistep syntheses.

Purpose of the Study:

• To present RENATE, a novel reaction-based de novo design tool.
• To introduce an inside-out design approach based on pseudo-retrosynthetic fragmentation.
• To validate the RENATE methodology by recreating approved drugs.

Main Methods:

• RENATE utilizes pseudo-retrosynthetic fragmentation of a reference ligand.
• Fragments are used to search for similar building blocks in a database.
• Building blocks are combined using reaction vectors to generate product molecules.
• A synthetic route is suggested for each generated product.

Main Results:

• The RENATE methodology was validated retrospectively by attempting to recreate approved drugs.
• RENATE successfully generated molecules that were highly similar or identical to the input drugs.
• The results validated the fragmentation, search, and design heuristics employed by the tool.

Conclusions:

• RENATE is an effective tool for reaction-based de novo molecular design.
• The inside-out approach and fragmentation strategy overcome challenges in multistep synthesis design.
• The tool's ability to recreate known drugs confirms its utility in generating synthetically accessible molecules.