Immortality is one of the main features of cancer cells. Tumor cells have an unlimited replicative potential, principally due to the holoenzyme telomerase. Telomerase is composed mainly by dyskerin (DKC1), a catalytic retrotranscriptase (hTERT) and an RNA template (hTR). The aim of this work is to develop new inhibitors of telomerase, selecting the interaction between hTR–DKC1 as a target. We designed two models of the human protein DKC1: homology and ab initio. These models were evaluated by different procedures, revealing that the homology model parameters were the most accurate. We selected two hydrophobic pockets contained in the PUA (pseudouridine synthase and archaeosine transglycosylase) domain, using structural and stability analysis. We carried out a docking-based virtual screen on these pockets, using the reported mutation K314 as the center of the docking. The hDKC1 model was tested against a library of 450,000 drug-like molecules. We selected the first 10 molecules that showed the highest affinity values to test their inhibitory activity on the cell line MDA MB 231 (Monroe Dunaway Anderson Metastasis Breast cancer 231), obtaining three compounds that showed inhibitory effect. These results allowed us to validate our design and set the basis to continue with the study of telomerase inhibitors for cancer treatment.

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 β 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.