In silico identification of a stable and drug-like Telomerase inhibitor originating from Celastrus hindsii

Introduction: Telomerase is reactivated in approximately 90% of human malignancies, underscoring its potential as a cancer-selective therapeutic target with minimal off-target toxicity. Natural products derived from medicinal plants represent a promising and underexplored source of novel telomerase inhibitors. Despite its longstanding empirical use in Vietnamese traditional medicine, Celastrus hindsii remains insufficiently characterized at the molecular level. Methods: In this study, we employed an integrated in silico framework to systematically evaluate C. hindsii-derived compounds for their telomerase-inhibitory potential. Results: Among the screened candidates, LTS0233892 emerged as the leading compound, exhibiting enhanced binding affinity and sustained interactions within the enzyme's catalytic site. Molecular dynamics simulations over 200 ns revealed that the telomerase-LTS0233892 complex maintained greater structural stability than the complex formed with the reference inhibitor, demonstrating an average backbone root mean square deviation (RMSD) of 0.348 ± 0.042 nm compared to 0.425 ± 0.068 nm for BIBR1532. Consistently, radius of gyration analysis indicated a more compact protein conformation upon LTS0233892 binding, yielding an average value of 2.932 ± 0.029 nm, compared to a slightly higher value of 2.972 ± 0.026 nm for the BIBR1532-bound system. Mechanistically, principal component analysis combined with free energy landscape reconstruction demonstrated that LTS0233892 stabilizes a more energetically favorable conformational ensemble of telomerase compared to BIBR1532. These results are consistent with MM/GBSA binding free energy calculations, in which LTS0233892 exhibited a binding free energy of –27.390 ± 4.028 kcal/mol, whereas BIBR1532 demonstrated a weaker binding energy of –20.996 ± 6.262 kcal/mol. Furthermore, LTS0233892 exhibited favorable drug-like properties, including optimal aqueous solubility and predicted oral bioavailability. Conclusion: Collectively, these computational findings indicate that LTS0233892 represents a promising small-molecule candidate warranting further experimental validation of its telomerase-inhibitory activity.