title: Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening, and Biochemical Assays.
abstract: Telomere maintenance is a universal cancer hallmark, and small molecules that disrupt telomere maintenance generally have anticancer properties. Since the vast majority of cancer cells utilize telomerase activity for telomere maintenance, the enzyme has been considered as an anticancer drug target. Recently, rational design of telomerase inhibitors was made possible by the determination of high resolution structures of the catalytic telomerase subunit from a beetle and subsequent molecular modeling of the human telomerase complex. A hybrid strategy including docking, pharmacophore-based virtual screening, and molecular dynamics simulations (MDS) were used to identify new human telomerase inhibitors. Docking methodology was applied to investigate the ssDNA telomeric sequence and two well-known human telomerase inhibitors' (BIBR1532 and MST-312) modes of interactions with hTERT TEN domain. Subsequently molecular dynamic simulations were performed to monitor and compare hTERT TEN domain, TEN-ssDNA, TEN-BIBR1532, TEN-MST-312, and TEN-ssDNA-BIBR1532 behavior in a dynamic environment. Pharmacophore models were generated considering the inhibitors manner in the TEN domain anchor site. These exploratory studies identified several new potent inhibitors whose IC50 values were generated experimentally in a low micromolar range with the aid of biochemical assays, including both the direct telomerase and the telomeric repeat amplification protocol (TRAP) assays. The results suggest that the current models of human telomerase are useful templates for rational inhibitor design.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences , Tehran, 14155-6451, Iran.|Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
authors.forename: Faezeh
authors.initials: F
authors.lastname: Shirgahi Talari
authors.affiliation: Razi Drug Research Center, Iran University of Medical Sciences , Tehran, 1449614535, Iran.
authors.forename: Kowsar
authors.initials: K
authors.lastname: Bagherzadeh
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences , Tehran, 14155-6451, Iran.
authors.forename: Sahand
authors.initials: S
authors.lastname: Golestanian
authors.affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Jarstfer
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences , Tehran, 14155-6451, Iran.
authors.forename: Massoud
authors.initials: M
authors.lastname: Amanlou
mesh_terms: D001681:Biological Assay; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D056004:Molecular Dynamics Simulation; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; C509186:TERT protein, human; D019098:Telomerase