Abstract
Telomerase, a reverse transcriptase enzyme involved in DNA synthesis, has a tangible role in tumor progression. Several studies have evidenced telomerase as a promising target for developing cancer therapeutics. The main reason is due to the overexpression of telomerase in cancer cells (85–90%) compared with normal cells where it is almost unexpressed. In this paper, we used a structure-based approach to design potential inhibitors of the telomerase active site. The MYSHAPE (Molecular dYnamics SHared PharmacophorE) approach and docking were used to screen an in-house library of 126 arylsulfonamide derivatives. Promising compounds were synthesized using classical and green methods. Compound 2C revealed an interesting IC50 (33 ± 4 µM) against the K-562 cell line compared with the known telomerase inhibitor BIBR1532 IC50 (208 ± 11 µM) with an SI ~10 compared to the BALB/3-T3 cell line. A 100 ns MD simulation of 2C in the telomerase active site evidenced Phe494 as the key residue as well as in BIBR1532. Each moiety of compound 2C was involved in key interactions with some residues of the active site: Arg557, Ile550, and Gly553. Compound 2C, as an arylsulfonamide derivative, is an interesting hit compound that deserves further investigation in terms of optimization of its structure to obtain more active telomerase inhibitors
Highlights
Accepted: 5 January 2022The nuclear protein complex, Telomere, defends the terminal ends of chromosomes from degradation, end-to-end fusion, and recombination [1,2,3]
Exploiting our previous experience and outcomes in the use of computational approaches [46,47,48,49,50], we developed a structure-based computational approach to performing a virtual screening of an in-house arylsulfonamides library
Starting from the PDB coordinates set of BIBR1532, a static pharmacophore model was created by using LigandScout containing six features (Figure 1A):
Summary
Accepted: 5 January 2022The nuclear protein complex, Telomere, defends the terminal ends of chromosomes from degradation, end-to-end fusion, and recombination [1,2,3]. After each cell division cycle, the telomere gradually shortens until the chromosomal DNA is exposed, inducing a DNA damage response [4,5]. This event helps to maintain the stability of genetic information and protects the genome in a “timebomb” manner [6]. When the length of telomeres reaches a critical point, cells reach the cycle of termination, aging, and death [5,6]. Normal cells cannot survive this progressive shortening. Cells can extend telomeres by reactivating telomerase activity or through a telomere replacement elongation mechanism (ALT) to help cells survive the crisis [7]. The reactivation of telomerase is observed in 85–90% of human tumor cells [8]
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