In vitro characterization and rational analog design of a novel inhibitor of telomerase assembly in MDA MB 231 breast cancer cell line

Tumor cells have unlimited replicative potential, principally due to telomerase activity, which requires assembly of components such as dyskerin (hDKC1), human telomerase reverse transcriptase and human telomerase RNA (hTR). The present study aimed to develop novel inhibitors of telomerase to target the interaction between hTR and hDKC1. Based on docking-based virtual screening, the candidates R1D2-10 and R1D2-15, which exert an in vitro inhibitory effect on telomerase activity, were selected. Human mammary adenocarcinoma MDA-MB 231 cell line was selected to evaluate the treatment with the aforementioned compounds; the effect on telomere length was evaluated by qPCR, where both compounds caused telomere shortening. Furthermore, expression of genes related to apoptosis and senescence process, as well SA beta galactosidase staining and caspase 3 activity. We determine that only compound R1D2-10 showed and effect on the induction of these cellular processes. To identify a lead compound from R1D2-10, 100 analogs were designed by LigDream server and then analyzed by AutoDock Vina and Protein-Ligand Interaction Profile to calculate their docking energy and target interaction. Those with the best values and specific residue interactions were selected for in silico prediction of absorption, distribution, metabolism, excretion (ADME), off-target interaction, toxicity and chemical diversity. A total of nine chemically different analogs was identified with higher docking affinity to the target, suitable ADME properties and not off-target interaction and side effects. These results indicated R1D2-10 and its analogs may serve as potential novel inhibitors of telomerase and antitumoral drugs in clinical use.

Automated summary

This study aimed to develop novel telomerase inhibitors and identified compound R1D2-10 and its analogs as potential inhibitors of telomerase and antitumoral drugs for clinical use. Through virtual screening and in silico prediction, nine chemically different analogs with suitable ADME properties and higher docking affinity to the target were identified. Compound R1D2-10 showed an effect on inducing cellular processes related to apoptosis and senescence, suggesting its potential as a lead compound in drug development.