In Silico Toxicity Assessment of Organophosphates: A DFT and Molecular Docking Study on Their Interaction with Human Serum Albumin (HSA)

  1. Tanya Singh
  2. Nisha Shankhwar
  3. Neeta Raj Sharma
  4. Anil Kumar
  5. Awadhesh Kumar Verma

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Abstract

This study presents an in silico analysis of the toxicity of Organophosphates (OPs) through their interaction with Human Serum Albumin (HSA) protein using density functional theory (DFT) and molecular docking approaches. Organophosphates, known for their widespread use as pesticides, have raised significant concerns due to their potential toxicological effects. To investigate the molecular mechanisms underlying OP toxicity, we conducted DFT calculations to determine the electronic properties and reactivity of selective OP compounds. Molecular docking simulations were performed to explore the binding affinity, interaction sites, and conformational changes of HSA upon exposure to OPs. The DFT analysis revealed key electronic descriptors, such as HOMO-LUMO gap and electrostatic potential, that indicate high reactivity of OPs with biological molecules. Docking results showed strong binding affinities between OPs and HSA, particularly at sites involved in metabolite and drug transport, suggesting potential interference with the protein’s native function. The interaction of OPs with HSA was further supported by molecular dynamics simulations, which confirmed the stability of the OP-HSA complex over time. These findings provide critical insights into the molecular basis of organophosphate toxicity, emphasizing the importance of their interaction with HSA. The combined DFT and molecular docking approach offers a valuable framework for predicting the toxicological behavior of OPs and lays the foundation for further in vitro and in vivo studies.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/15107047.

    Organophosphates are widely used as pesticides in agriculture, but their potential toxicity to humans, through various exposure routes, remains a significant concern. Understanding the mechanisms underlying OP toxicity is crucial for developing safer alternatives and effective mitigation strategies. The study identified specific binding affinities and modes of interaction for a set of OP compounds with HSA. In terms of advancing the field, such a study provides a computational framework for prioritizing experimental studies of OP toxicity.

    In terms of advancing the field, such a study provides a computational framework for prioritizing experimental studies of OP toxicity.

    Major issues

    • The study limitedly focused on HSA interactions as a primary indicator of toxicity, while HSA binding is important for understanding the pharmacokinetics and distribution of OPs, their toxicity primarily stems from the inhibition of acetylcholinesterase. Therefore, solely focusing on HSA interactions provides an incomplete picture of OP toxicity. The study demonstrates that different OPs can bind to different sites on HSA. It would be beneficial to explore potential HSA binding site specificity among the chosen OPs to broaden the study's scopeList significant concerns about the research, if there are any.

    Minor issues

    • The study involved limited scope of DFT calculations but exploring other relevant molecular descriptors, such as electrostatic potential, polarizability, and chemical reactivity parameters could enrich the analysis and provide a more comprehensive understanding of organophosphate toxicity.

    Competing interests

    The author declares that they have no competing interests.

  2. Version published to 10.1101/2024.12.15.628551v3 on bioRxiv
  3. Version published to 10.1101/2024.12.15.628551v2 on bioRxiv
  4. Version published to 10.1101/2024.12.15.628551v1 on bioRxiv