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Screening, docking, and molecular dynamics analysis of Mitragyna speciosa (Korth.) compounds for targeting HER2 in
Nabila Hadiah Akbar1, Farendina Suarantika2, Taufik Muhammad Fakih3
1Pharmacist Professional Education Study Program (PPSP), Faculty of Mathematics and Natural Sciences, Universitas Lambung Mangkurat, Jl. Brig Jend. Hasan Basri, Banjarmasin, South Kalimantan, 70123, Indonesia.
Abstract:
Breast cancer remains the most commonly diagnosed cancer among women worldwide, with approximately 2.3 million new cases reported in 2022. In the United States alone, an estimated 310,720 new cases of female breast cancer are expected in 2024. HER2-positive breast cancer, characterized by the overexpression of the human epidermal growth factor receptor 2 (HER2), accounts for about 20 % of all breast cancer cases. The development of anti-HER2 therapies has significantly improved survival rates for patients with HER2-positive breast cancer. In this study, we employed in silico methods to evaluate the potential of natural alkaloids, Mitragynine and 7-Hydroxymitragynine, as HER2 inhibitors. Molecular docking revealed binding energies of -7.56 kcal/mol and -8.77 kcal/mol, respectively, with key interactions involving residues such as Leu726, Val734, Ala751, Lys753, Thr798, and Asp863. Molecular dynamics simulations demonstrated the stability of all three complexes, including Mitragynine, 7-Hydroxymitragynine, and Native (SYR127063), over the simulation period. Mitragynine exhibited stronger interaction stability, supported by a higher hydrogen bond occupancy of 39.19 %, compared to 4.32 % for 7-Hydroxymitragynine, while Native (SYR127063) displayed the highest occupancy at 49.66 %. MM-PBSA analysis further validated these findings, with Native (SYR127063) exhibiting the most favorable total binding energy of -163.448 ± 17.288 kJ/mol, followed by Mitragynine at -112.33 ± 22.41 kJ/mol, and 7-Hydroxymitragynine at -103.56 ± 15.61 kJ/mol. ADMET, physicochemical properties, and drug-likeness evaluations indicated that all compounds satisfy Lipinski, Ghose, Veber, Egan, and Muegge rules, confirming their suitability as lead-like molecules. Based on these findings, Mitragynine and 7-Hydroxymitragynine are promising candidates for HER2-targeted breast cancer therapy, with further experimental validation recommended to confirm their clinical potential.
Insights
Natural alkaloids Mitragynine and 7-Hydroxymitragynine show potential as HER2 inhibitors for breast cancer therapy. Computational studies indicate favorable binding and drug-like properties, suggesting further investigation for clinical use.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Breast cancer is a leading global cancer in women, with HER2-positive subtypes requiring targeted therapies.
- Existing anti-HER2 treatments have improved survival rates, but novel therapeutic strategies are continuously sought.
- Natural compounds offer a promising avenue for developing new anti-cancer agents.
Purpose of the Study:
- To investigate the potential of natural alkaloids, Mitragynine and 7-Hydroxymitragynine, as inhibitors of the HER2 receptor.
- To evaluate the binding affinity, stability, and drug-likeness of these alkaloids using in silico methods.
Main Methods:
- Molecular docking simulations to assess binding energies and interactions with the HER2 receptor.
- Molecular dynamics simulations to evaluate the stability of drug-receptor complexes.
- MM-PBSA analysis to calculate binding free energies.
- ADMET and physicochemical property predictions to assess drug-likeness.
Main Results:
- Mitragynine and 7-Hydroxymitragynine exhibited significant binding energies to HER2, with key interactions at specific amino acid residues.
- Molecular dynamics simulations confirmed the stability of the complexes, with Mitragynine showing stronger interaction stability.
- MM-PBSA analysis indicated favorable binding energies for both alkaloids, with Native (SYR127063) showing the most favorable energy.
- All compounds satisfied established drug-likeness rules (Lipinski, Ghose, Veber, Egan, Muegge).
Conclusions:
- Mitragynine and 7-Hydroxymitragynine demonstrate potential as novel HER2 inhibitors for breast cancer treatment.
- These natural alkaloids possess favorable in silico drug-like properties, making them promising lead compounds.
- Further experimental studies are warranted to validate their efficacy and safety for clinical application in HER2-positive breast cancer therapy.
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