Binding af nity and structural dynamics of amygdalin-HER2 interactions: An investigation for breast cancer therapy

Breast cancer refers to the uncontrolled growth of epithelial cells originating from the ducts or lobules. The malignancy is initially characterized by a painless lump, followed by swelling, itching, and redness in the breast area. With approximately 2.1 million cases per year, breast cancer is considered the most prevalent malignancy worldwide. Nevertheless, most cancer cases go unreported in developed countries. High mortality rates are observed in least-developed countries, particularly in Asia and Africa, due to limited access to quality prevention, early diagnosis, and treatment options. In Tanzania, breast cancer ranks second to cervical cancer, accounting for 10% of all cancer cases documented in 2020. The disease poses a significant threat due to high mortality rates and its ability to affect both men and women.

Breast cancer is a heterogeneous disease classified into subtypes based on the presence of hormone receptors such as estrogen, progesterone, and human epidermal growth factor receptor (HER) 2 (HER2).

These classifications help to determine appropriate treatment strategies. The HER2 receptor belongs to the epidermal growth factor receptor (EGFR) family, consisting of 4 transmembrane receptor tyrosine kinases: HER1, HER2, HER3, and HER4. The family plays a vital role in regulating cell growth, proliferation, and differentiation through complex signaling pathways. It is also associated with specific subsets of breast cancer. Unlike other receptors in the EGFR family, HER2 is overexpressed in 20 %–25 % of breast cancer cases. Such overexpression is associated with aggressive tumor progression and poor prognosis if left untreated. HER2 consists of 3 distinct regions: an N-terminal extracellular domain, a single α-helix transmembrane domain, and an intracellular tyrosine kinase domain. The N-terminal extracellular domain, the largest region at approximately 100 ​kDa, contains 4 subdomains (I-IV) (Fig. 1). The extracellular region of HER2 is a crucial target for cancer therapy because of an easy accessibility and a central role in receptor activation. The overexpression in tumor cells makes the region an ideal target for therapeutic drugs, as evidenced by the success of treatments like trastuzumab. The extracellular domain also mediates receptor dimerization, a critical step in HER2 signaling. Targeting this area allows inhibition of receptor activation at an early stage, offering a more direct and specific approach than focusing on the interior intracellular kinase domain.

Two main strategies have been developed to block the HER2 overexpression: monoclonal antibodies and small molecules that inhibit tumor progression. These small molecules are designed to target specific molecules or pathways involved in cancer growth and metastasis. Natural compounds are increasingly gaining attention for their potential in breast cancer treatment due to their abundance, accessibility, and effectiveness. Natural product compounds have been integral to medicine since 2600 BCE, with approximately 700 drugs from natural sources documented during that period. A major breakthrough in utilizing naturally derived medicines came with the discovery of vinca alkaloids from Catharanthus roseus, which set a precedent for the development of market-approved therapeutic agents. Initially explored for diabetes treatment, these alkaloids underwent rigorous testing and evaluation, ultimately gaining recognition as effective therapeutic agents. Over the past decades, natural products have contributed to about 30% of approved formulations, highlighting their potential in modern medicine. Phytochemicals, including flavonoids, alkaloids, terpenes, and others, offer promising properties for cancer inhibition. Among the diverse class of phytochemicals, cyanogenic glycosides have gained attention for their potential anticancer effects. One well-known example is amygdalin (Fig. 2), a compound found in rosaceous species, particularly their seeds, such as almonds and apples, which have demonstrated therapeutic potential in cancer control. Recent studies have highlighted the ability to decrease the viability of HER2-positive SK-BR-3 breast cancer cells, suggesting a possible role in targeting tumors afflicted by HER2 overexpression. Amygdalin has shown the ability to modulate apoptotic regulators by upregulating the pro-apoptotic protein Bax and downregulating the anti-apoptotic protein Bcl-2 in leukemia, cervical, liver, and prostate cancer cells. Additionally, experimental studies have demonstrated an increased lifespan in amygdalin-treated cancer-bearing animals, along with a notable reduction in the spread of pulmonary metastasis. These findings highlight the therapeutic promise of amygdalin in cancer treatment. Despite promising findings from experimental studies, the direct inhibition of HER2 by amygdalin has not been extensively reported. Therefore, this study aims to explore the interactions, considering the critical role of HER2 overexpression in aggressive breast cancer subtypes. In this study, we employed computational approaches to elucidate the interactions between amygdalin and HER2, using molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations.