Can we integrate plasma protein binding data into IATA using new approach methodologies? A case study on bisphenol...

Area of Science:

• Toxicology
• Biochemistry
• Computational Chemistry

Background:

• Bisphenol A (BPA) substitutes are increasingly used, but safety data, especially toxicological evaluations, are limited.
• Plasma protein binding (PPB) is a critical factor in toxicokinetics and toxicodynamics, influencing chemical safety assessments.

Purpose of the Study:

• To investigate the plasma protein binding (PPB) characteristics of 18 bisphenol analogs.
• To develop and validate a quantitative structure-property relationship (QSPR) model for predicting PPB.
• To assess the utility of biomimetic high-performance liquid chromatography (HSA-HPLC) and computational methods for PPB evaluation.

Main Methods:

• Biomimetic high-performance liquid chromatography with human serum albumin coated column (HSA-HPLC) was employed for experimental PPB determination.
• A quantitative structure-property relationship (QSPR) model was developed using molecular descriptors (van der Waals surface area, minimum projection area, isoelectric point charge).
• Molecular docking simulations were performed to analyze binding interactions with human serum albumin.

Main Results:

• All 18 bisphenol analogs exhibited very high plasma protein binding (>94%), with notable differences among structural isomers.
• A validated QSPR model accurately predicted PPB values and identified key molecular determinants.
• Molecular docking provided insights into binding site preferences and stabilizing interactions with human serum albumin.

Conclusions:

• The integrated approach using HSA-HPLC, QSPR modeling, and docking simulations offers a reliable and human-relevant strategy for PPB assessment.
• Accurate PPB data is crucial for enhancing in vitro to in vivo extrapolation (IVIVE).
• This integrated strategy supports the use of PPB data in chemical safety assessments within integrated approaches to testing and assessment (IATA).