Abstract

Background: Telomerase is a reverse transcriptase that maintains the length of telomere in cells. Human telomerase reverse transcriptase (hTERT) is one of the two basic components of telomere, consists of four domains and is an important target for inhibiting cell proliferation in malignant tumours. Human telomerase reverse transcriptase consists of 1132 amino acids that form four different domains. Amino acid residue from position 58 to 197 represents the GQ motif of Telomerase Essential N-Terminal domain (TEN) domain of hTERT. GQ governs the interaction between hTR and TERT. Similarly, CP motif present in TRBD domain is made of helix α3 followed by a loop. CP together with T motif ensures proper assembly of telomerase ribonucleotide complex. Controlling telomerase can help in ceasing cell proliferation in cancerous tissue. Thus, identifying hTERT inhibitory molecules can be used to design anticancer drugs.

Objective: The main purpose of the study is to identify molecules that can inhibit motifs present in domains of hTERT.

Method: The 3D structure of hTERT was modeled using I-TASSER server and the energy minimized structure was validated using overall quality factor (ERRAT) and Ramachandran plot. Using hierarchical virtual screening, zinc natural database was screened against Telomerase Essential N-Terminal domain (TEN) and Telomerase RNA Binding Domain (TRBD) domains of modeled hTERT, ADME filtering, DFT analysis and molecular dynamics Studies.

Results: The molecule ZINC13142555 had the best glide score and energy and was chosen for density functional analysis to study its electronic properties. The stability of hTERT- ZINC13142555 was studied through molecular dynamics simulation for a period of 10ns. The identified compounds show interaction with GQ and CP motifs and hence it can be further proceeded to drug discovery process.

Keywords: Telomerase, hTERT, docking, molecular dynamics, density functional theory, inhibitors.

Graphical Abstract