In silico Evaluation of Pharmacokinetics, Pharmacodynamics, and Safety Profile of Telomestatin Analogues for the Treatment of Cancer

Introduction: Telomestatin is known for its potent telomerase inhibition and anticancer activity; however, its clinical translation has been hindered by poor pharmacokinetic properties. In this study, we aimed to evaluate the pharmacokinetics, toxicity, and G-quadruplex binding affinity of telomestatin analogues using a suite of computational tools. Methods: The ADME profiles of the telomestatin analogues were assessed using SwissADME, ADMETlab, and vNN, which predict physicochemical properties, pharmacokinetics, and druglikeness. The toxicity profiles of the compounds were predicted using the ProTox-II server, which provides LD₂⁽ values, toxicity class assignments, and potential effects on stress-response pathways. Finally, binding affinities between the analogues and the G-quadruplex structure were evaluated using AutoDock Tools 1.5.6. Results: Computational ADME analyses showed that the telomestatin analogues possessed low gastrointestinal absorption, suggesting that oral administration would not be suitable. Compounds TN9–TN14 did not exhibit P-gp substrate activity, a desirable property for cytotoxic drugs. Predicted LD₂⁽ values ranged from 800 to 1210 mg/kg. Docking studies indicated that TN9 had the strongest binding affinity toward the G-quadruplex, with a binding energy of – 10.08 kcal/mol. Discussion: Among the analogues evaluated, TN9 demonstrated the most favorable overall profile, including desirable pharmacokinetic predictions, a benign toxicity profile, and strong binding affinity. These findings suggest that TN9 warrants further investigation in in vitro and in vivo systems to assess its pharmacokinetics, safety, and anticancer efficacy. Conclusion: Telomestatin analogues, particularly TN9, display promising characteristics and should be further explored as potential anticancer agents.