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Identifying natural products for gastric cancer treatment through pharmacophore creation, 3D QSAR, virtual screening,
Zeinab Jalali1, Samad Nejad Ebrahimi2, Hassan Rezadoost1
1Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Evin, 1983963113, Tehran, Iran.
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.
Insights
Researchers identified novel lead compounds with potential anti-gastric cancer effects through virtual screening and molecular docking. These compounds show promise for future gastric cancer therapy development, offering an alternative to existing treatments.
Area of Science:
- Computational chemistry
- Drug discovery
- Oncology
Background:
- Gastric cancer (GC) is a leading cause of cancer death worldwide, often diagnosed at late stages.
- Current treatments have limitations and side effects, driving interest in novel therapeutic strategies.
- Traditional medicinal plants are being explored for potential anti-cancer properties.
Purpose of the Study:
- To identify novel compounds with anti-gastric cancer activity using computational methods.
- To develop a pharmacophore and 3D-QSAR model for anti-gastric cancer compounds.
- To virtually screen a large database for potential drug candidates.
Main Methods:
- Generation of pharmacophore models and 3D-QSAR using 50 known anti-GC compounds.
- Virtual screening of 183,885 compounds against identified pharmacophore hypotheses.
- Molecular docking of selected compounds with protein targets (7BKG, 4F5B, 4ZT1).
- ADME/Tox property prediction and molecular dynamic simulations.
Main Results:
- 21 lead compounds were identified with high docking scores ( -13.366 to -6.404 kcal/mol).
- These compounds met established criteria for drug-likeness (MW < 500 g/mol, logP, H-bond donors/acceptors).
- Molecular dynamics simulations confirmed the stability of top ligand-receptor complexes.
Conclusions:
- The identified lead compounds exhibit significant potential for anti-gastric cancer activity.
- These compounds represent promising candidates for further development in gastric cancer therapy.
- This study highlights the utility of computational approaches in drug discovery for challenging diseases.
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