Tehran University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening, and Biochemical Assays Publisher Pubmed



Shirgahi Talari F1, 3 ; Bagherzadeh K2 ; Golestanian S1 ; Jarstfer M3 ; Amanlou M1
Authors
Show Affiliations
Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, 14155-6451, Iran
  2. 2. Razi Drug Research Center, Iran University of Medical Sciences, Tehran, 1449614535, Iran
  3. 3. Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, 27599, NC, United States

Source: Journal of Chemical Information and Modeling Published:2015


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. © 2015 American Chemical Society.
Related Docs
View other Related Docs
1. Combined Virtual Screening, Dft Calculations and Molecular Dynamics Simulations to Discovery of Potent Mmp-9 Inhibitors, Letters in Drug Design and Discovery (2019)
2. A New Insight Into Mushroom Tyrosinase Inhibitors: Docking, Pharmacophore-Based Virtual Screening, and Molecular Modeling Studies, Journal of Biomolecular Structure and Dynamics (2015)
3. Prediction of Dual Agents As an Activator of Mutant P53 and Inhibitor of Hsp90 by Docking, Molecular Dynamic Simulation and Virtual Screening, Journal of Molecular Graphics and Modelling (2015)
4. A Comparative Study Based on Docking and Molecular Dynamics Simulations Over Hdac-Tubulin Dual Inhibitors, Journal of Molecular Graphics and Modelling (2016)
5. Erp57 Protein Activators for Management of Fertility by Virtual Screening and Molecular Dynamic Studies, Biointerface Research in Applied Chemistry (2023)
6. Discovery of Potential Anti-Ischemic Stroke Agents Through Inhibiting Sulfonylurea Receptor 1 (Sur1): A Pharmacophore-Based Screening, Docking, and Molecular Dynamic Simulation, Biointerface Research in Applied Chemistry (2022)
7. Structure-Based Virtual Screening for Defeating Drug Resistant Form of Egfr Protein, Combinatorial Chemistry and High Throughput Screening (2016)
8. Tetracyclines As a Potential Antiviral Therapy Against Crimean Congo Hemorrhagic Fever Virus: Docking and Molecular Dynamic Studies, Computational Biology and Chemistry (2017)
Experts (# of related papers)
View all Related Experts
Massoud Amanlou (22)
Nima Rezaei (1)
Other Related Docs
9. Epigenetic-Based Cancer Therapeutics: New Potential Hdac8 Inhibitors, Journal of Biomolecular Structure and Dynamics (2022)
10. Autophagy Induction Reduces Telomerase Activity in Hela Cells, Mechanisms of Ageing and Development (2017)
11. Deletion of Loop Fragment Adjacent to Active Site Diminishes the Stability and Activity of Exo-Inulinase, International Journal of Biological Macromolecules (2016)
12. Fragment Pharmacophore-Based Screening: An Efficient Approach for Discovery of New Inhibitors of Toll-Like Receptor 5, Combinatorial Chemistry and High Throughput Screening (2016)
13. Prediction of New Hsp90 Inhibitors Based on 3,4-Isoxazolediamide Scaffold Using Qsar Study, Molecular Docking and Molecular Dynamic Simulation, DARU# Journal of Pharmaceutical Sciences (2017)
14. Molecular Perception of Interactions Between Bis(7)Tacrine and Cystamine-Tacrine Dimer With Cholinesterases As the Promising Proposed Agents for the Treatment of Alzheimers Disease, Journal of Biomolecular Structure and Dynamics (2016)
15. Spheroid-Derived Cells From Renal Adenocarcinoma Have Low Telomerase Activity and High Stem-Like and Invasive Characteristics, Frontiers in Oncology (2019)
16. 3D-Qsar, Molecular Docking, and Molecular Dynamic Simulations for Prediction of New Hsp90 Inhibitors Based on Isoxazole Scaffold, Journal of Biomolecular Structure and Dynamics (2018)
17. Synthesis of Some Spiro Indeno[1,2-B]Pyrido[2,3-D]Pyrimidine-5,3′ - Indolines As New Urease Inhibitors, Iranian Journal of Pharmaceutical Research (2016)
18. Zeolite Nanoparticles Inhibit Aβ-Fibrinogen Interaction and Formation of a Consequent Abnormal Structural Clot, ACS Applied Materials and Interfaces (2016)
19. Identification of Phytochemicals Targeting C-Met Kinase Domain Using Consensus Docking and Molecular Dynamics Simulation Studies, Cell Biochemistry and Biophysics (2018)
20. Repurposing of the Approved Small Molecule Drugs in Order to Inhibit Sars-Cov-2 S Protein and Human Ace2 Interaction Through Virtual Screening Approaches, Journal of Biomolecular Structure and Dynamics (2022)
21. In Silico Docking of Medicinal Herbs Against P. Gingivalis for Chronic Periodontitis Intervention, International Dental Journal (2025)
22. Discovery of Novel Dual Inhibitors Against Mdm2 and Mdmx Proteins by in Silico Approaches and Binding Assay, Life Sciences (2016)
23. Identification of New Hsp90 Inhibitors: Structure Based Virtual Screening, Molecular Dynamic Simulation, Synthesis and Biological Evaluation, Anti-Cancer Agents in Medicinal Chemistry (2021)
24. Structure-Based Pharmacophore Design and Virtual Screening for Novel Potential Inhibitors of Epidermal Growth Factor Receptor As an Approach to Breast Cancer Chemotherapy, Molecular Diversity (2018)
25. Identification of New Dna Gyrase Inhibitors Based on Bioactive Compounds From Streptomyces: Structure-Based Virtual Screening and Molecular Dynamics Simulations Approaches, Journal of Biomolecular Structure and Dynamics (2020)
26. An Update on Phytochemicals in Molecular Target Therapy of Cancer: Potential Inhibitory Effect on Telomerase Activity, Current Medicinal Chemistry (2016)
27. Anti-Hcv and Anti-Malaria Agent, Potential Candidates to Repurpose for Coronavirus Infection: Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation Study, Life Sciences (2020)
28. Improved Drug Delivery and Therapeutic Efficacy of Pegylated Liposomal Doxorubicin by Targeting Anti-Her2 Peptide in Murine Breast Tumor Model, European Journal of Pharmaceutical Sciences (2016)
29. Analysis of B-Rafv600einhibitors Using 2D and 3D-Qsar, Molecular Docking and Pharmacophore Studies, Molecular Diversity (2015)
30. Indole Alkaloids As Potential Candidates Against Covid-19: An in Silico Study, Journal of Molecular Modeling (2022)
31. New Heat Shock Protein (Hsp90) Inhibitors, Designed by Pharmacophore Modeling and Virtual Screening: Synthesis, Biological Evaluation and Molecular Dynamics Studies, Journal of Biomolecular Structure and Dynamics (2020)
32. Nanocurcumin-Mediated Down-Regulation of Telomerase Via Stimulating Tgfβ1 Signaling Pathway in Hepatocellular Carcinoma Cells, Iranian Biomedical Journal (2018)
33. The Penicillin Binding Protein 1A of Helicobacter Pylori, Its Amoxicillin Binding Site and Access Routes, Gut Pathogens (2021)
34. Human Il-2Rα Subunit Binding Modulation of Il-2 Through a Decline in Electrostatic Interactions: A Computational and Experimental Approach, PLoS ONE (2022)
35. Targeting the Vital Non-Structural Proteins (Nsp12, Nsp7, Nsp8 and Nsp3) From Sars-Cov-2 and Inhibition of Rna Polymerase by Natural Bioactive Compound Naringenin As a Promising Drug Candidate Against Covid-19, Journal of Molecular Structure (2023)
36. 3D-Qsar and Docking Studies on Adenosine A2a Receptor Antagonists by the Comfa Method, SAR and QSAR in Environmental Research (2015)
37. Arylhydrazone Derivatives of Naproxen As New Analgesic and Anti-Inflammatory Agents: Design, Synthesis and Molecular Docking Studies, Journal of Molecular Graphics and Modelling (2016)
38. Inhibition of Liver Alanine Aminotransferase and Aspartate Aminotransferase by Hesperidin and Its Aglycone Hesperetin: An in Vitro and in Silico Study, Life Sciences (2017)
39. The Importance of the Non-Active Site and Non-Periodical Structure Located Histidine Residue Respect to the Structure and Function of Exo-Inulinase, International Journal of Biological Macromolecules (2017)