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.

journal_name

J Chem Inf Model

authors

Shirgahi Talari F,Bagherzadeh K,Golestanian S,Jarstfer M,Amanlou M

doi

10.1021/acs.jcim.5b00336

subject

Has Abstract

pub_date

2015-12-28 00:00:00

pages

2596-610

issue

12

eissn

1549-9596

issn

1549-960X

journal_volume

55

pub_type

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