Identification of potent inhibitors targeting Tribolium castaneum GSTe2 via structure-based screening and molecular dynamics simulation

Abstract

Red flour beetle, Tribolium castaneum, has a major negative impact during storage of agricultural products and reveals the negative impacts on human health. Insect-specific epsilon glutathione S-transferase (GSTs) which requires reduced glutathione (GSH) as an essential substrate not only develop insecticide resistance but also play important role in insect metamorphosis. Inhibition of the insect metamorphosis and the development of insecticide resistance could play an important role in pest control, so T. castaneum GSTe2 (TcGSTe2) in our previous study could be an important target protein for this purpose. This study aimed to find a potential TcGSTe2 inhibitors through in silico mothods, including molecular modeling, molecular docking, ADMET assay, followed by molecular dynamics (MD) simulation, principal component analysis and MM/PBSA analysis. The results showed that ZINC000169293362 and ZINC000095566957 were selected as potential TcGSTe2 inhibitors with high-binding affinity and without any toxicity from 3618 of GSH-like compounds obtained from ZINC database. MD simulation results revealed that TcGSTe2-ZINC000169293362 had more stability than that of reference GSH. Moreover, TcGSTe2-ZINC000169293362 and TcGSTe2-ZINC000095566957 showed lower binding free energy (−27.53 ± 0.16 kcal/mol and −18.83 ± 0.15 kcal/mol, respectively) compared with TcGSTe2-GSH (−8.90 ± 0.30 kcal/mol). This study could provide new insight into reduction of insecticide resistance and be used to design new inhibitors of insect GSTs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Glutathione S-transferase
• molecular docking
• molecular dynamics simulation
• virtual screening
• Tribolium castaneum

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 32070501 and 32170521).

Disclosure statement

The authors report there are no competing interests to declare.

Author contributions

KumChol Kim: conceptualization, methodology, investigation, validation, writing original draft; Wenjing Zhang: investigation; Peng Chen: validation; Chengjun Li: investigation, validation; Bin Li: conceptualization, funding acquisition, project administration, supervision, writing-review and editing.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (No. 32070501 and 32170521).