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

Myungwon Seo,Ha Ryong Kim,Chong Hak Chae,Yuno Lee,Jongwoon Kim

doi:10.3390/toxics9030059

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.

Highlights

Biocides are used extensively industrially, professionally, and personally to control harmful organisms
Biocides associated with pulmonary fibrosis were predicted based on the two intersecting adverse outcome pathway (AOP) (AOP 347) using molecular initiating event (MIE) modeling methods
In the AOP 347, we showed that the quantitative structure-activity relationship (QSAR) model is a more competent method to predict biocide prediction than the molecular dynamics (MD) and pharmacophore modeling

Summary

Introduction

Biocides are used extensively industrially, professionally, and personally to control harmful organisms. According to the European Union’s (EU) Biocidal Products Regulation (BPR) [2] and South Korea’s “Household Chemical Products and Biocides Safety Act (or K-BPR) [3]” for biocide regulation, the toxicological effects in mixture of chemicals, namely additivity, synergism, and antagonism, of biocidal products should be considered when approving a biocide. Mixture toxicity effects occur when the mixture components interact. Data on synergistic toxicity effects among mixture components are lacking [6,7]. Conducting toxicity tests for all mixtures conventionally can be an economic burden to the chemical industry and unfeasible because the number of conceivable mixture combinations is extremely large

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