Novel QSAR Models for Molecular Initiating Event Modeling in Two Intersecting Adverse Outcome Pathways Based Pulmonary Fibrosis Prediction for Biocidal Mixtures.

ABSTRACT

The adverse outcome pathway (AOP) was introduced as an alternative method to avoid unnecessary animal tests. Under the AOP framework, an in silico methods, molecular initiating event (MIE) modeling is used based on the ligand-receptor interaction. Recently, the intersecting AOPs (AOP 347), including two MIEs, namely peroxisome proliferator-activated receptor-gamma (PPAR-γ) and toll-like receptor 4 (TLR4), associated with pulmonary fibrosis was proposed. Based on the AOP 347, this study developed two novel quantitative structure-activity relationship (QSAR) models for the two MIEs. The prediction performances of different MIE modeling methods (e.g., molecular dynamics, pharmacophore model, and QSAR) were compared and validated with in vitro test data. Results showed that the QSAR method had high accuracy compared with other modeling methods, and the QSAR method is suitable for the MIE modeling in the AOP 347. Therefore, the two QSAR models based on the AOP 347 can be powerful models to screen biocidal mixture related to pulmonary fibrosis.