Mining Medicinally Relevant Bioreduction Substrates Inspired by Ligand-Based Drug Design

Area of Science:

• Biocatalysis
• Medicinal Chemistry
• Computational Chemistry

Background:

• Biocatalytic transformations often require enzyme structures or extensive experimentation.
• Expanding substrate scope for bioreduction, like carrot-mediated processes, is crucial for discovering new drug candidates.
• Current methods for identifying suitable substrates are often time-consuming and labor-intensive.

Purpose of the Study:

• To develop a practical, cost-effective method for predicting biocatalytic bioreduction substrates without prior enzyme structural information.
• To expand the substrate scope of carrot-mediated bioreduction for identifying novel, medicinally relevant ketones.
• To leverage principles from ligand-based drug design for biocatalysis screening.

Main Methods:

• Literature data analysis and the construction of pharmacophore and reactivity prediction models.
• Screening of a virtual library exceeding 8000 ketones containing common drug discovery heterocycles (N, O, S) and functional groups.
• Experimental validation of predicted substrates to confirm expanded bioreduction scope.

Main Results:

• Successfully expanded the substrate scope of carrot-mediated bioreduction.
• Identified and validated novel ketone substrates suitable for biocatalytic transformation.
• Developed predictive models that can efficiently screen large ketone libraries.

Conclusions:

• Medicinal chemistry principles can effectively address general biocatalysis challenges, such as substrate scope prediction.
• The developed screening workflow is time-, labor-, and cost-saving for evaluating bioreduction substrates.
• Publicly available models and the straightforward workflow facilitate the application of biocatalysis in medicinal chemistry.