In eukaryotes, the intrinsic limitations of DNA polymerases prevent the complete replication of the terminal ends of linear chromosomes during genome duplication. Consequently, each replication cycle results in progressive DNA shortening due to the removal of the RNA primers at the chromosome ends1,2. Telomeres function as specialized nucleoprotein assemblies that preserve chromosome integrity by shielding terminal regions from degradation and illegitimate recombination3. They typically comprise approximately 1,000 – 2,000 tandem repeats of a short DNA motif that adopts a T-loop configuration, reinforced by a protruding 3′ guanine-enriched single-stranded extension to ensure end stability4,5,6. Progressive telomere attrition to a critical threshold subsequently activates DNA damage signaling pathways, culminating in apoptosis or cellular senescence2. If these checkpoints are bypassed, continued telomere attrition can promote genomic instability and facilitate tumorigenesis7.

Malignant cells circumvent the proliferative limits imposed by telomere shortening through reactivation of telomerase, a specialized complex that elongates telomeric DNA during genome duplication8. This enzyme functions as a ribonucleoprotein complex with reverse transcriptase activity, playing a central role in preserving chromosome-end integrity and maintaining genomic stability9. In human cells, the holoenzyme comprises two principal components: a catalytic protein subunit with reverse transcriptase activity (TERT) and an RNA molecule (telomerase RNA, TR) that provides the template sequence required for telomere repeat synthesis10. Dysregulated elevation of telomerase activity contributes to tumor initiation and progression across a broad spectrum of cancers, including those of the breast, kidney, colorectum, cervix, lung, liver, pancreas, thyroid, prostate, and bladder11,12,13. Notably, telomerase reactivation is detected in approximately 85–90% of human cancers, underscoring its pivotal role in oncogenesis14,15. As such, pharmacological inhibition of telomerase represents a compelling therapeutic strategy with broad applicability across cancer types7,16. Moreover, telomerase expression is low or undetectable in most normal somatic cells, making telomerase inhibitors potentially more selective and less cytotoxic than conventional chemotherapeutics, which often indiscriminately affect both cancerous and healthy tissues17.

BIBR1532 has been developed as a highly specific telomerase inhibitor and a potential anticancer agent18. This compound selectively targets the catalytic TERT subunit of telomerase, thereby effectively suppressing telomerase activity18. Previous research demonstrated that BIBR1532 exhibits potent antitumor efficacy across various cancer types, including ovarian cancer, chondrosarcoma, breast cancer, lung cancer, and germ cell tumors19. However, pharmacokinetic limitations, such as poor bioavailability and metabolic instability, remain significant challenges for its clinical translation20,21,22,23. Such constraints reinforce the importance of developing novel small-molecule telomerase inhibitors. In recent years, in silico approaches have emerged as powerful tools for accelerating the discovery of novel therapeutic agents, particularly during the early stages of drug development24,25. Compared with conventional experimental screening methods, which are typically time-consuming and resource-intensive, computational strategies enable the rapid screening of large compound libraries. Moreover, techniques such as molecular docking, molecular dynamics simulations, and binding free energy calculations provide mechanistic insights into protein–ligand interactions at the atomic level26,27. These approaches support the identification of potential lead compounds and allow the evaluation of binding stability, conformational dynamics, and interaction mechanisms prior to experimental validation. Importantly, integrating molecular docking with molecular dynamics simulations improves prediction reliability by accounting for protein flexibility and solvent effects, which are often neglected in static docking models28,29. In addition, in silico methods help reduce failure rates in drug discovery by prioritizing compounds with favorable pharmacokinetic and toxicity profiles through early-stage ADMET prediction30,31. Therefore, such strategies represent a cost-effective and efficient alternative to traditional high-throughput screening methods, particularly for identifying natural products as potential inhibitors of key therapeutic targets such as telomerase.

Over the past decade, increasing attention has been directed toward herbal species and natural extracts as alternative or complementary approaches for cancer treatment. Numerous natural compounds have been identified with the capacity to inhibit telomerase activity32,33,34. Owing to their structural diversity and pharmacological richness, medicinal herbs represent a promising reservoir for the discovery of novel telomerase-targeting agents. In Vietnam, Celastrus hindsii is a widely used medicinal plant in traditional medicine, particularly in northern provinces such as Quang Ninh and Ninh Binh35. In traditional practices of the Muong ethnic group, C. hindsii is employed to treat a variety of conditions, including chronic diseases, inflammation, ulcers, and cancer36,37. However, its use remains largely empirical, and the bioactive compounds responsible for its purported anticancer effects, as well as their molecular mechanisms, have not been scientifically characterized. To date, no studies have investigated the telomerase-inhibitory potential of C. hindsii. In this study, we performed virtual screening of natural compounds derived from C. hindsii to identify candidates targeting telomerase. This computational approach facilitates the rapid identification of compounds with strong and stable binding affinities to telomerase, thereby highlighting promising candidates for further development as telomerase inhibitors.

The expression of telomerase is recognized as a hallmark of many cancer types, making it a highly attractive therapeutic target over the past decade57,58. Telomerase has been widely recognized as an effective therapeutic target in various cancers, offering reduced side effects due to its selective targeting of cancer cells over normal cells59,60. Despite these promising findings, no telomerase-targeting drug has yet been approved by the FDA for broad-spectrum cancer treatment61. Therefore, the ongoing search for novel molecules capable of effectively inhibiting telomerase remains of critical importance. From a functional perspective, the biological consequences of telomerase inhibition have been well characterized. Compounds such as BIBR1532 have been shown to induce progressive telomere shortening, ultimately leading to growth arrest and cellular senescence in cancer cells62. Furthermore, inhibition of telomerase can disrupt telomere integrity and activate DNA damage response pathways, thereby enhancing the sensitivity of cancer cells to therapeutic interventions63. These findings underscore the central role of telomere maintenance in cancer progression and treatment response64. The compound BIBR1532 has been developed as a telomerase inhibitor by tightly binding to key amino acid residues within its binding motif. However, certain mutations within the BIBR1532 binding site of telomerase have been implicated in human diseases65,66. The residues involved in this region are known to play essential roles in ligand recognition and stabilization, highlighting their importance as anchoring sites for the rational design of more effective inhibitors.

In this context, the interaction of LTS0233892 with key residues within the active site of telomerase suggests its potential to elicit similar biological effects, likely disrupting telomerase function (Figure 9). LTS0233892 exhibits an interaction pattern comparable to that of BIBR1532, while maintaining a more distributed interaction network across the binding pocket. This observation is consistent with previous studies on telomerase inhibitors and their derivatives, which indicate that effective inhibition is governed by cooperative interactions with multiple residues rather than a single dominant contact. Such a distributed interaction pattern stabilizes the ligand within the binding pocket and reinforces the overall binding free energy landscape. In addition, this multi-residue engagement may buffer the impact of local structural perturbations, thereby reducing the likelihood of resistance arising from point mutations67,68,69. From a structural perspective, the chemical features of LTS0233892 further support its binding efficiency through its ability to form both hydrogen bonds and hydrophobic interactions (Table 1), which are known to enhance binding adaptability within a dynamic protein environment. These characteristics contribute to the sustained interaction stability observed in our molecular dynamics analyses and are consistent with established structure–activity relationship studies of telomerase inhibitors70,71. Specifically, the presence of multiple stabilizing contacts may promote persistent ligand anchoring within the binding pocket, thereby minimizing conformational fluctuations and maintaining favorable binding conformations over time. This behavior is further supported by the consistent interaction profiles and energy contributions observed throughout the simulation trajectory.

Consequently, LTS0233892 demonstrates strong potential to inhibit telomerase activity, likely through a mechanism that parallels that of BIBR1532 by directly interfering with the assembly of active enzyme subunits72. Moreover, LTS0233892 appears to outperform BIBR1532 by maintaining greater intramolecular stability and distributing its binding energy more evenly across multiple residues within the binding pocket (Figure 9). These characteristics are particularly advantageous in cancer therapy, where sustained and stable inhibition of telomerase is critical73,74. Consistent with these observations, our findings demonstrate that LTS0233892, identified from C. hindsii, has stronger binding affinity and stability than BIBR1532, which has not been previously reported. In addition, LTS0233892 exhibits predicted pharmacokinetic properties, including solubility and oral bioavailability, which may support its suitability for continued study. According to our investigation using the LOTUS database38, LTS0233892 has been reported in both C. hindsii and Salacia chinensis, a medicinal plant widely used in traditional medicine75. However, despite extensive screening of natural products, the potential interaction of LTS0233892 with telomerase has not yet been described34, and its natural abundance remains unclear. Therefore, further studies on its extraction, quantification, and structural characterization are needed. Importantly, experimental validation will be required to confirm its potential effects on telomerase activity and to assess its biological relevance.

From a broader biological perspective, beyond its predicted direct inhibitory effects, telomerase suppression may also trigger a range of downstream cellular responses. Telomerase inhibition has been associated with progressive telomere shortening, telomere dysfunction, and activation of DNA Damage Response pathways, potentially reflected by markers such as γ-H2AX, p53, and p21, which are closely linked to cell cycle arrest and cellular senescence76,77,78. Beyond its canonical role, the catalytic subunit TERT is known to participate in non-telomeric functions, including regulation of DNA repair, oxidative stress balance, and transcriptional programs. Therefore, inhibition of TERT may impair DNA repair capacity, increase reactive oxygen species (ROS) levels, and disrupt oncogenic signaling pathways79,80. However, the extent to which these mechanisms are associated with LTS0233892 remains unclear. Further experimental studies are therefore necessary to elucidate its broader biological effects, particularly the downstream consequences of telomerase inhibition and their cellular implications.

Although current computational approaches provide valuable insights, several limitations should be acknowledged. While MDS captures atomic-level motions to a certain extent, it may not fully reflect the complexity of protein–ligand interactions under physiological conditions in living systems. In addition, predicted pharmacokinetic and toxicity profiles from ADMET models are based on computational estimations and may not fully account for critical factors such as metabolism, bioavailability, and off-target effects, which remain difficult to predict accurately without experimental validation. Furthermore, the present study focuses on a single molecular target, telomerase, whereas cancer progression is governed by complex, multi-target biological networks. Consequently, potential off-target interactions and broader system-level effects of LTS0233892 have not been explored. Therefore, although our findings provide a useful preliminary framework for understanding the interaction between LTS0233892 and telomerase, they should be interpreted with caution. Further experimental studies, including biochemical assays, cell-based models, and in vivo investigations, are required to validate the predicted activity and comprehensively evaluate its therapeutic potential.

This study identifies LTS0233892, a compound derived from C. hindsii, as a novel small-molecule inhibitor targeting telomerase. Molecular dynamics–based analyses, including RMSD, PCA, FEL, and binding free energy calculations, consistently indicated a stronger binding affinity of LTS0233892 compared with BIBR1532. In parallel, pharmacokinetic and toxicity profiling suggested favorable drug-like properties and an acceptable safety profile, underscoring its potential for further development. This integrated in silico strategy provides mechanistic insights into the interactions between LTS0233892 and key residues within the telomerase binding pocket, supporting its capacity to interfere with enzymatic function. Nevertheless, these findings remain limited to computational predictions. The absence of experimental validation, together with the inherent approximations of molecular docking and molecular dynamics simulations, warrants careful interpretation. Future studies should therefore prioritize biochemical and cellular assays to validate the telomerase inhibitory activity of LTS0233892, as well as to elucidate its effects on telomere dynamics, DNA damage responses, and cancer cell proliferation. Furthermore, additional work is required to isolate and quantify this compound from C. hindsii, and to evaluate its pharmacological efficacy and safety in vitro and in vivo. These efforts will be crucial in determining whether LTS0233892 can be advanced as a viable telomerase-targeted anticancer agent.

BBB: blood–brain barrier; BFE: Binding free energy; FEL: free energy landscape; MDS: Molecular dynamics simulations; NPT: isothermal–isobaric; NVT: Volume-Temperature; PCA: Principal component analysis; PDB: Protein Data Bank; PLIP: Protein–Ligand Interaction Profiler; PME: Particle Mesh Ewald; Rg: radius of gyration; RMSD: root mean square deviation; ROS: reactive oxygen species; SASA: solvent accessible surface area; TERT: reverse transcriptase; TR: telomerase RNA

This work is a part of the research project CSA.2025.063 funded by Saigon University. The authors gratefully acknowledge this financial support.

All authors read and approved the final manuscript.

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The authors declare that they have not used any generative AI (a type of artificial intelligence technology that can produce various types of content including text, imagery, audio and synthetic data.)

The authors declare that they have no competing interests.