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Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening,
Faezeh Shirgahi Talari1,2, Kowsar Bagherzadeh3, Sahand Golestanian1
1Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences , Tehran, 14155-6451, Iran.
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.
Insights
Researchers identified new anticancer drugs targeting telomerase, an enzyme crucial for cancer cell survival. This discovery aids in developing novel therapies by providing effective human telomerase inhibitors.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Telomere maintenance is a key cancer characteristic.
- Telomerase is a validated anticancer drug target due to its role in most cancers.
- Recent structural data enables rational design of telomerase inhibitors.
Purpose of the Study:
- To identify novel human telomerase inhibitors using computational and experimental methods.
- To validate computational models for drug design against telomerase.
Main Methods:
- Hybrid computational strategy: docking, pharmacophore screening, and molecular dynamics simulations (MDS).
- Investigated interactions between telomeric DNA, known inhibitors (BIBR1532, MST-312), and the hTERT TEN domain.
- Experimental validation using biochemical assays, including telomerase and TRAP assays.
Main Results:
- Identified several potent new inhibitors of human telomerase.
- Achieved IC50 values in the low micromolar range experimentally.
- Confirmed the utility of computational models for inhibitor design.
Conclusions:
- The developed computational models are effective for rational design of human telomerase inhibitors.
- New inhibitors show promise for anticancer drug development.
- This approach advances the targeting of telomerase for cancer therapy.
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