Navigating chemical reaction space - application to DNA-encoded chemistry

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Drug discovery

Background:

• Selecting reactions for synthesizing small molecule screening libraries, like DNA-encoded libraries (DELs), is a significant big data challenge due to the vast number of available reactions.
• Existing methods often struggle to efficiently navigate and select appropriate reactions compatible with DEL synthesis constraints, such as avoiding damage to the genetic barcode.

Purpose of the Study:

• To develop a computational workflow, Reaction Navigator, for navigating chemical reaction space and facilitating the selection of suitable reactions for DNA-encoded library (DEL) synthesis.
• To enable efficient identification of reactions based on user-defined criteria, independent of specific substitution patterns.

Main Methods:

• Utilized the open-source KNIME Analytics Platform to process reaction files from a large chemistry database.
• Implemented a customizable filtering cascade to remove reactions incompatible with DEL synthesis.
• Developed a clustering approach based on user-defined molecular reaction descriptors to organize and search reaction space.

Main Results:

• Successfully mapped chemical reaction space for aromatic aldehydes, identifying reactions applicable to DEL synthesis.
• Demonstrated the successful translation of exemplary reactions to DNA-tagged substrates for library synthesis.
• Showcased the workflow's versatility by mapping reaction space for amines and data from a second database, under various reaction conditions.

Conclusions:

• Reaction Navigator provides an effective computational solution for navigating complex reaction spaces in the context of DNA-encoded library design.
• The workflow enhances the efficiency and applicability of reaction selection for creating diverse and functional small molecule libraries.
• The developed methodology is adaptable and can be applied to different starting materials, reaction conditions, and chemical databases.