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Identifying natural products for gastric cancer treatment through pharmacophore creation, 3D QSAR, virtual screening, and molecular dynamics studies

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Abstract

Background

Gastric cancer (GC) is known as the fourth leading cause of cancer-related death and the fifth major cancer in the world, and this is a serious threat to general health all over the world. The lack of early detection markers results in a belated diagnosis, i.e. the final stages, which could be associated with the ineffectiveness of the treatment strategies, and naturally, it leads to poor prognosis. Even though a variety of treatments have been developed, there is a trend of studying traditional medicinal plants, due to the worrying side effect of drugs available in the market.

Methods

In this study, pharmacophore generation and 3D-QSAR model were created using 50 compounds with anti-gastric cancer activity (with IC50 had been reported in the previous studies).

Results

Based on three of the best pharmacophoric hypotheses, virtual screening was performed to discover the top anti-gastric cancer compounds from a database of 183,885 compounds. The selected compounds were used for molecular docking with three protein receptors 7BKG, 4F5B, and 4ZT1 to investigate the intermolecular interactions between these ligands and receptors. Finally, 21 lead compounds with the highest amount of docking score ranging from − 13.366 to -6.404 kcal/mol were selected, and then the ADME/Tox properties of these compounds were calculated. All these compounds have a fitness score above 1.8, a molecular weight of less than 500 g/mol, hydrogen bond donors up to 3, hydrogen bond acceptors up to 8.50, and logP of 1.013 to 4.174. Finally, molecular dynamic simulations for top-scoring ligand-receptor complexes were investigated.

Conclusion

These selected lead compounds have the most anti-gastric cancer effects among the 183,885 compounds in the database. Therefore, lead compounds might be considered for gastric cancer therapy in future studies.

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Data availability

The data will be available upon request.

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Acknowledgements

We thank gratefully Dr. Mansour Zahedi and Dr. Bahare Noohi’s efforts and technical support of the Chemistry Computational Center at Shahid Beheshti University. We’re also grateful to Kosar Jalali for her diligent work editing this manuscript.

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Authors and Affiliations

  1. Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Evin, 1983963113, Tehran, Iran

    Zeinab Jalali, Samad Nejad Ebrahimi & Hassan Rezadoost

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  1. Zeinab Jalali
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  2. Samad Nejad Ebrahimi
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  3. Hassan Rezadoost
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Contributions

Zeinab Jalali did the molecular modeling part and prepared the draft of the manuscript. Samad N Ebrahimi supervised the project. Samad N Ebrahimi and Hassan Rezadoost finalized the manuscript. All authors have approved the paper.

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Correspondence to Samad Nejad Ebrahimi.

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Jalali, Z., Nejad Ebrahimi, S. & Rezadoost, H. Identifying natural products for gastric cancer treatment through pharmacophore creation, 3D QSAR, virtual screening, and molecular dynamics studies. DARU J Pharm Sci 31, 243–258 (2023). https://doi.org/10.1007/s40199-023-00480-0

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