Citation:

Lalone, C., D. Blatz, M. Jensen, S. Vliet, S. Mayasich, K. Mattingly, T. Transue, W. Melendez, A. Wilkinson, C. Simmons, C. Ng, C. Zhang, AND Y. Zhang. From Protein Sequence to Structure: The Next Frontier in Cross-Species Extrapolation for Chemical Safety Evaluations. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 42(2):463-474, (2023). https://doi.org/10.1002/etc.5537

Impact/Purpose:

Technology continues to advance that allows scientists to more rapidly understand complicated biology. There are now computer programs that allow drug companies to look at the structure of a chemical and a chemical target found in the body of humans and rapidly determine whether that chemical has the potential to be useful as a drug. That chemical then becomes a candidate for drug development and moves forward with more extensive laboratory testing, which is quite costly. Drug companies use these state-of-the-art computer programs as an initial screening to save them time and money and reduce the chance that they start developing a drug that will not work as intended. These computer tools hold great promise in advancing our understanding of whether or not a chemical could interact with a target in other non-human species as well. This understanding could be useful for identifying chemicals that could cause harm to animals or plants in the environment. The US EPA has developed a tool called Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) that helps to understand which organisms might be most susceptible to a given chemical based on how similar the chemical targets are in the body. For hundreds of species that cannot be tested the SeqAPASS tool provides a yes or no answer to the question of whether or not a particular chemical target exists in another species. However, there is interest in understanding how susceptible one species is compared to another species and being able to provide a quantitative measure of susceptibility across species. Therefore, we have begun to explore and develop a means to make the SeqAPASS predictions more numerical using the computer programs commonly applied to chemical screening in the drug development industry. This manuscript describes a computational pipeline and results from that pipeline in expanding the SeqAPASS analysis to generate quality protein structures and compare structures across species as another line of evidence toward conservation to be used in species extrapolation.

Description:

Computational screening for potentially bioactive molecules using advanced molecular modeling approaches including molecular docking and molecular dynamic simulation is mainstream in certain fields like drug discovery. Significant advances in computationally predicting protein structures from sequence information have also expanded the availability of structures for nonmodel species. Therefore, the objective of the present study was to develop an analysis pipeline to harness the power of these bioinformatics approaches for cross-species extrapolation for evaluating chemical safety. The Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool compares protein-sequence similarity across species for conservation of known chemical targets, providing an initial line of evidence for extrapolation of toxicity knowledge. However, with the development of structural models from tools like the Iterative Threading ASSEmbly Refinement (ITASSER), analyses of protein structural conservation can be included to add further lines of evidence and generate protein models across species. Models generated through such a pipeline could then be used for advanced molecular modeling approaches in the context of species extrapolation. Two case examples illustrating this pipeline from SeqAPASS sequences to I-TASSER-generated protein structures were created for human liver fatty acid–binding protein (LFABP) and androgen receptor (AR). Ninety-nine LFABP and 268 AR protein models representing diverse species were generated and analyzed for conservation using template modeling (TM)-align. The results from the structural comparisons were in line with the sequence-based SeqAPASS workflow, adding further evidence of LFABL and AR conservation across vertebrate species. The present study lays the foundation for expanding the capabilities of the web-based SeqAPASS tool to include structural comparisons for species extrapolation, facilitating more rapid and efficient toxicological assessments among species with limited or no existing toxicity data.

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