Molecular Modeling and Evaluation of Novel Dibenzopyrrole Derivatives as Telomerase Inhibitors and Potential Drug for Cancer Therapy

Abstract

During previous years, many studies on synthesis, as well as on anti-tumor, anti-inflammatory and anti-bacterial activities of the pyrazole derivatives have been described. Certain pyrazole derivatives exhibit important pharmacological activities and have proved to be useful template in drug research. Considering importance of pyrazole template, in current work the series of novel inhibitors were designed by replacing central ring of acridine with pyrazole ring. These heterocyclic compounds were proposed as a new potential base for telomerase inhibitors. Obtained dibenzopyrrole structure was used as a novel scaffold structure and extension of inhibitors was done by different functional groups. Docking of newly designed compounds in the telomerase active site (telomerase catalytic subunit TERT) was carried out. All dibenzopyrrole derivatives were evaluated by three docking programs: CDOCKER, Ligandfit docking (Scoring Functions) and AutoDock. Compound C_9g, C_9k and C_9l performed best in comparison to all designed inhibitors during the docking in all methods and in interaction analysis. Introduction of pyrazole and extension of dibenzopyrrole in compounds confirm that such compound may act as potential telomerase inhibitors.

Carbazole scaffolds in cancer therapy: a review from 2012 to 2018

“…Carbazole derivatives bearing diamine groups presented a new potential for telomerase inhibition. Using three different docking programs (CDOCKER, Ligandfit, Autodock) and interaction analysis demonstrated that compounds 14a and 14b (Figure 20) had the best telomerase inhibition activity more interestingly with the introduction of a pyrazole ring 48 .…”

Structural, functional, and stability change predictions in human telomerase upon specific point mutations

“…19 provided the first structural model of human telomerase, using computational methods derived from the X-ray structure of the full-length T.castaneum telomerase (PDB: 3DU6; apo form) 11 and the enzyme in complex with a RNA∶DNA hairpin (PDB: 3KYL) 32 . In the present study, we used the TERT catalytic subunit of the human telomerase model 19 and defined/predicted the active-site residues based on T. castaneum telomerase structure 11,33–35 (Fig. 1A).…”

“…1A) 19 .

Figure 1( A ) The structure of the catalytic subunit (TERT) and active-site residues in Tribolium castaneum (PDB: 3DU6) 11 and the human 19 telomerase model. ( B ) The structure of ligand molecules, namely, C_9i 33 , C_9k 33 , 16A 34 , and NSC749234 36 , which were selected to study with human telomerase.

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“…Four recently designed or identified telomerase inhibitors, namely, C_9i 33 , C_9k 33 , 16A 34 , and NSC749234 36 , were selected to study with the mutated human telomerase model (Fig. 1B).…”

“…1B). The C_9i and C_9k compounds are derivatives of dibenzopyrrole, and in silico analysis of this new chemical scaffold has shown potential telomerase-binding properties 33 . Compound 16A 34 is from a series of novel aryl-2h-pyrazole derivatives containing an oxygen-bearing heterocyclic group.…”