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Identification of phytochemicals from genus Potentilla as estrogen receptor-α inhibitors through molecular docking,
Amit Kumar1, Nehal Purohit1, Praval Pratap Singh2
1Natural Product Chemistry Laboratory, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India.
Abstract:
Breast cancer is among the most prevalent causes of death in women worldwide. About 70-75% of these cancers are hormone-dependent, expressing estrogen receptors (ERs), mainly ER-α, making it an essential target for managing breast cancer. Potentilla genus has been traditionally used worldwide for its diverse biological activities, including antidiabetic, anti-inflammatory, antioxidant, etc. In the present study, phytochemicals isolated from various species of the Potentilla species were evaluated for their in silico ER-α inhibitory activity through molecular docking, molecular dynamic simulation, Density Functional Theory calculations and free energy calculations. Four hundred seventy-one molecules were used through ligand preparation and docked inside the generated grid on ER-α protein cavity and the standard drug tamoxifen. Fourteen molecules have shown better dock (-14.42 to -12.57 kcal/mol) scores than tamoxifen (-10.71 kcal/mol). Most of the molecules belong to the category of flavonoid glycosides. Molecules with good binding free energy (-78.81 to -12.94 kcal/mol) indicate stability inside the binding pocket. Further, based on dock score, pharmacokinetic parameters, and binding free energy, two hit molecules, 1 and 2, were selected for their molecular dynamic simulation, MM/PBSA and DFT calculations for assessing their stability and structural dynamics inside the binding cavity as well as their reactivity. Through MD simulation analysis, it was evaluated that Compound 1 could distort the protein to a greater extent. In contrast, compound 2 was stable throughout the simulation time of 150 ns and can be further explored in vitro and in vivo studies as ER-α inhibitors in breast cancer.
Insights
Potentilla phytochemicals show promise as estrogen receptor-alpha (ER-α) inhibitors for breast cancer treatment. Computational studies identified potent flavonoid glycosides with better binding affinity than tamoxifen, warranting further investigation.
Area of Science:
- Medicinal Chemistry
- Computational Biology
- Pharmacology
Background:
- Breast cancer is a leading cause of death in women, with 70-75% of cases being hormone-dependent and expressing estrogen receptors (ERs), primarily ER-α.
- The Potentilla genus possesses diverse traditional medicinal uses, including anti-inflammatory and antioxidant properties, suggesting potential therapeutic applications.
Purpose of the Study:
- To computationally evaluate phytochemicals from Potentilla species for their inhibitory activity against ER-α.
- To identify novel ER-α inhibitors for breast cancer therapy using molecular docking and simulation techniques.
Main Methods:
- Docking of 471 Potentilla-derived molecules against the ER-α protein cavity.
- Molecular dynamic simulations, MM/PBSA, and Density Functional Theory (DFT) calculations for top-ranked compounds.
- Pharmacokinetic parameter analysis and binding free energy calculations.
Main Results:
- Fourteen molecules exhibited superior docking scores compared to the standard drug tamoxifen.
- Flavonoid glycosides were the predominant class among the identified potent inhibitors.
- Two hit molecules, Compound 1 and Compound 2, demonstrated significant binding affinity and stability, with Compound 2 showing particular promise for further study.
Conclusions:
- Potentilla phytochemicals, particularly flavonoid glycosides, represent a promising source of novel ER-α inhibitors.
- Compound 2 warrants further in vitro and in vivo investigation as a potential therapeutic agent for ER-α-positive breast cancer.
