SeqAPASS

SeqAPASS evaluates protein sequence conservation across species to enable extrapolation of chemical susceptibility and toxicity information from model organisms to other taxa.

Key Features:

• Protein Target Conservation Evaluation: Uses sequence alignment to assess conservation of protein targets across thousands of species to support cross-species toxicity extrapolation.
• Enhanced Data Synthesis and Visualization: Versions 2.0–6.1 include customizable data visualizations and comprehensive summary reports for data synthesis and interpretation.
• Application in New Approach Methodologies (NAMs): Evaluates amino acid sequence conservation for NAMs and has been applied to type 3 iodothyronine deiodinase (DIO3) to identify amino acids critical for thyroid hormone binding and cofactor interaction.
• Variant Protein Design and Testing: Aids design of variant proteins via site-directed mutagenesis for expression in cell culture and in vitro testing of chemical inhibition.
• Molecular Modeling and Docking: Integrates with Molecular Operating Environment (MOE) to construct protein models (e.g., human DIO3), perform in silico mutagenesis, and run virtual docking, with affinity scores that may have limited resolution for ranking inhibitor potency.

Scientific Applications:

• Cross-species Toxicity Extrapolation: Infers relative intrinsic chemical susceptibility across taxa using conserved protein-target information.
• Regulatory Decision Support and Risk Assessment: Provides evidence to inform ecotoxicology, risk assessment, and regulatory evaluations of chemical effects across species.
• Target-specific Mechanistic Assessment: Supports investigation of chemical effects on specific protein targets across species to elucidate mechanisms of action.
• NAM Development and Experimental Design: Guides design of variant proteins and targeted experiments to reduce reliance on vertebrate animal testing.

Methodology:

Computational methods explicitly include sequence alignment-based protein sequence conservation analysis, molecular modeling using Molecular Operating Environment (MOE), in silico mutagenesis, virtual docking, and generation of customizable data visualizations and summary reports.