Combined In Vitro and In Silico Workflow to Deliver Robust, Transparent, and Contextually Rigorous Models of...

Area of Science:

• Toxicology and computational chemistry
• Development of New Approach Methodologies (NAMs)

Background:

• Increasing need for efficient and resource-conscious chemical safety assessment.
• Existing data gaps and limitations in traditional toxicology testing methods.

Purpose of the Study:

• To describe a New Approach Methodologies (NAMs) workflow integrating in vitro bioassays and in silico computational models.
• To introduce the concept of explicit "purpose contexts" for in silico model development.
• To enhance chemical safety assessment by improving efficiency and accuracy.

Main Methods:

• Integration of an in vitro high-throughput bioassay measuring fluorescent probe displacement from transthyretin (TTR).
• Development of three explicit "purpose contexts" for in silico model development.
• Creation of a quantitative structure-activity relationship (QSAR) model based on derived purpose contexts.

Main Results:

• Established a workflow combining in vitro and in silico methods for toxicology.
• Defined purpose contexts to guide mechanistic interpretation, validation, and output design of in silico models.
• Developed a robust QSAR model with improved in vitro hit rates and in silico learning potential.

Conclusions:

• The proposed NAMs workflow and purpose contexts enhance the development and application of in silico models in toxicology.
• This approach offers a more transparent, mechanistic, and efficient strategy for chemical safety assessment.
• The integrated workflow promises to reduce costs and improve the prioritization of chemical libraries for bioactivity testing.