Tehran University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! By
Computational Studies on Structural Aspects of Pyrazolo[3,4-B]Pyridine Derivatives As Trka Inhibitors in Cancer Therapy Publisher Pubmed



D Gheidari DAVOOD ; M Mehrdad MORTEZA ; K Jani KIMYA ; A Feizkhah ALIREZA
Authors

Source: Scientific Reports Published:2025


Abstract

Tropomyosin receptor kinases (TRKs) play a crucial role in nerve development, and their dysregulation due to genetic alterations, such as NTRK fusions, has been linked to various cancers. Recently, TRKs have emerged as effective therapeutic targets. However, resistance to these therapies presents significant challenges. In this study, a series of pyrazolo[3,4-b]pyridine derivatives were analyzed to generate pharmacophore-based models, conduct molecular docking, perform molecular dynamics (MD) simulations, and evaluate absorption, distribution, metabolism, excretion, and toxicity (ADMET). The generated pharmacophore hypothesis, ADRR_1, identified essential characteristics required for biological activity. Molecular docking was carried out on 37 ligands, yielding docking scores ranging from −12.672 to −14.169 kcal/mol. The best fit was observed for ligand L5, which formed five conventional hydrogen bonds with residues Glu546, Met620, Lys627, and Lys572. Additionally, three carbon-hydrogen bonds were established between the pyrazolo[3,4-b]pyridine moiety and residues Gly623, Glu618, and Asp703. MD simulations further confirmed the stability of the TRKA-L5 complex, underscoring the robust interactions between L5 and the target protein. The virtual screening study used 453 ligands from the ZINC database and identified the hit ligand ZINC000013331109, which exhibited a docking score of −10.775 kcal/mol and demonstrated good binding affinity with key amino acids. All screened ZINC hits adhered to the Lipinski Rule of Five (Ro5), and notably, ZINC000013331109 did not exhibit hepatotoxicity, unlike the top-scoring ligands and entrectinib, which were associated with liver toxicity. This study highlights the potential of ZINC000013331109 as a promising candidate for TRKA inhibition. Further research is warranted to explore the efficacy and safety of this ligand in clinical settings. © 2025 Elsevier B.V., All rights reserved.
Related Docs
View other Related Docs
1. 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)
2. Synthesis, in Vitro and in Silico Screening of 2-Amino-4-Aryl-6-(Phenylthio) Pyridine-3,5-Dicarbonitriles As Novel Α-Glucosidase Inhibitors, Bioorganic Chemistry (2020)
3. Identification of Natural Inhibitors Against Cdk6 Target Using Pharmacophore-Based Screening, Molecular Docking, Molecular Dynamic Simulations, and Quantitative Electrostatic Potential Analysis Maps: A Comprehensive Study, Computational Biology and Chemistry (2025)
Experts (# of related papers)
View all Related Experts
Massoud Amanlou (6)
Mohammad Ali Faramarzi (4)
Other Related Docs
4. Drug Repurposing for Targeting Fibronectin in Treatment of Endometriosis and Cancers, Journal of Biomolecular Structure and Dynamics (2023)
5. Synthesis and Biological Evaluation of 12-Aryl-11-Hydroxy-5,6-Dihydropyrrolo[2″,1″:3′,4′]Pyrazino[1′,2′:1,5]Pyrrolo[2,3-D]Pyridazine-8(9H)-One Derivatives As Potential Cytotoxic Agents, ACS Omega (2023)
6. 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)
7. Design and Synthesis of Novel Quinazolinone-Pyrazole Derivatives As Potential Α-Glucosidase Inhibitors: Structure-Activity Relationship, Molecular Modeling and Kinetic Study, Bioorganic Chemistry (2021)
8. Design, Synthesis, Biological Evaluation, and Molecular Modeling Studies of Pyrazole-Benzofuran Hybrids As New Α-Glucosidase Inhibitor, Scientific Reports (2021)
9. 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)
10. Synthesis of 4-Alkylaminoimidazo[1,2-A]Pyridines Linked to Carbamate Moiety As Potent Α-Glucosidase Inhibitors, Molecular Diversity (2021)
11. Synthesis, Cyp 450 Evaluation, and Docking Simulation of Novel 4-Aminopyridine and Coumarin Derivatives, Archiv der Pharmazie (2019)
12. Discovery of Novel Dual Inhibitors Against Mdm2 and Mdmx Proteins by in Silico Approaches and Binding Assay, Life Sciences (2016)
13. Combined Virtual Screening, Dft Calculations and Molecular Dynamics Simulations to Discovery of Potent Mmp-9 Inhibitors, Letters in Drug Design and Discovery (2019)
14. Binding Mode of Triazole Derivatives As Aromatase Inhibitors Based on Docking, Protein Ligand Interaction Fingerprinting, and Molecular Dynamics Simulation Studies, Research in Pharmaceutical Sciences (2017)
15. Synthesis, Molecular Docking Study, and Cytotoxic Activity of 1,3,5-Triaryl Pyrazole Derivatives, Letters in Drug Design and Discovery (2016)
16. Discovery of Novel Pyrazolo[1,5-A]Pyrimidine Derivatives As Potent Reversal Agents Against Abcb1-Mediated Multidrug Resistance, European Journal of Medicinal Chemistry (2024)
17. 3D-Qsar and Docking Studies on Adenosine A2a Receptor Antagonists by the Comfa Method, SAR and QSAR in Environmental Research (2015)
18. Triarylpyrazole Derivatives As Potent Cytotoxic Agents; Synthesis and Bioactivity Evaluation Pyrazole Derivatives As Anticancer Agent, Drug Research (2021)
19. Synthesis, Characterization and Biological Evaluation of Novel 3-Methyl-5-Pyrazolone Derivatives, Journal of Medicinal and Chemical Sciences (2021)
20. Computational Design of Trkb Peptide Inhibitors and Their Biological Effects on Ovarian Cancer Cell Lines, International Journal of Peptide Research and Therapeutics (2016)