Human epidermal growth factor receptor 2 (HER2)-positive breast cancer represents approximately 20% of breast cancer diagnoses worldwide and is historically associated with aggressive disease biology and poorer prognoses. Even as therapies like trastuzumab (Herceptin; Genentech), pertuzumab (Perjeta; Genentech), and other tyrosine kinase inhibitors have revolutionized outcomes, challenges with drug resistance and harmful effects still pose issues. This leads to a need for novel therapeutic approaches.1
Natural products, long regarded as a source of drug discovery, are now being re-examined. A new study published in Current Research in Structural Biology explored the anti-HER2 effect of two alkaloids derived from Mitragyna speciosa (or kratom), mitragynine and 7-hydroxymitragynine (7-OH). They used tests, including molecular docking, molecular dynamics simulations, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, to explore these possible effects.1
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The investigators reported that both mitragynine and 7-OH demonstrated stable binding affinity with the HER2 receptor. Docking analysis showed binding energies of –7.56 kcal/mol for mitragynine and –8.77 kcal/mol for 7-OH, with interactions observed at key residues such as Leu726, Val734, Ala751, Lys753, Thr798, and Asp863.¹ These results suggest that both compounds could effectively occupy HER2’s active site, potentially disrupting oncogenic signaling pathways. Molecular dynamics simulations demonstrated the stability of all 3 complexes, including mitragynine, 7-OH, and native (SYR127063), over the simulation period.1
Further binding free energy validation using the MM-PBSA method supported these findings. SYR127063, the control variable, exhibited the strongest binding, while mitragynine and 7-OH showed moderately strong affinities. Importantly, both compounds satisfied multiple drug-likeness rules, including Lipinski, Ghose, Veber, Egan, and Muegge filters, and demonstrated favorable ADMET properties, indicating their potential as viable lead molecules for further preclinical investigation.1,2
These results align with broader work in oncology to use natural compounds as cancer-fighting tools. Past research has shown the worth of plant-based chemicals as sources of bioactive molecules that can modulate cell signaling, apoptosis, and angiogenesis in cancer models. The chance for mitragynine and its byproduct to act as HER2 blockers is notable, given how much dependence there is on biologic treatments and the need for small-molecule alternatives that may cost less and be more accessible.
For pharmacists, these early-stage findings are important. Although the data remain strictly computational and require extensive laboratory validation, they highlight the role of computational drug discovery in oncology. Pharmacists should be aware of new natural product-based therapies, as these compounds may soon enter preclinical tests and lead to new oral HER2 inhibitors. Since mitragynine and 7-OH are main compounds of kratom, pharmacists must also keep an eye on regulatory considerations and the need to differentiate between recreational kratom use and carefully derived pharmaceutical applications.
Mitragynine and 7-OH from Mitragyna speciosa demonstrate promising early results in silico activity against HER2 and possess favorable drug traits and pharmacokinetic profiles. Although these findings are not ready for clinical recommendations, they set the base for further laboratory validation and may lead to new drug development. If these compounds work well in future clinical studies, they may represent an innovative natural product–based strategy for overcoming resistance and improving outcomes in HER2-positive breast cancer.