In Silico Design, Synthesis, and Biological Evaluation of Anticancer Arylsulfonamide Endowed with Anti-Telomerase Activity

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

Synthesis, In Vitro and In Silico Analysis of New Oleanolic Acid and Lupeol Derivatives against Leukemia Cell Lines: Involvement of the NF-κB Pathway

“…The MM-GBSA approach employs molecular mechanics, the generalized Born model, and the solvent accessibility method to elicit free energies from structural information circumventing the computational complexity of free-energy simulations wherein the net free energy is treated as a sum of a comprehensive set of individual energy components, each with a physical basis [ 55 ]. The conformational entropy change—TΔS—can be computed by normal-mode analysis on docking poses, but many authors have reported that the lack of the evaluation of the entropy is not critical for calculating the MM-GBSA (or MM-PBSA) free energies for similar systems [ 56 , 57 , 58 , 59 , 60 ]. For these reasons, the entropy term–TΔS was not calculated to reduce computational time.…”

Deciphering the Potential of Pre and Pro-Vitamin D of Mushrooms against Mpro and PLpro Proteases of COVID-19: An In Silico Approach

“…We discovered stable compounds and used the final ten nanoseconds of data for analysis, and snapshots were taken at every 100 picoseconds. The entropy term −TΔS was not calculated to reduce computational time, as previously reported [ 43 , 44 , 45 ].…”

Investigating the Inhibition of FTSJ1 a Tryptophan tRNA-Specific 2′-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR

“…Three MD simulation replicas of 100 ns each were carried out using a Desmond 6.5 [24] using the OPLS4 force field for each complex FTSJ1/DAP, FTSJ1/SAM, and FTSJ1/NV848, NV914, and NV930. The system setup and the simulation options are the same as reported in previous manuscripts [25][26][27][28]. Initial velocities were determined with random seeds.…”