Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking, molecular dynamic simulation and virtual screening

Abbasi, Maryam; Sadeghi‐Aliabadi, Hojjat; Hassanzadeh, Farshid; Amanlou, Massoud

doi:10.1016/j.jmgm.2015.08.001

Cited by 15 publications

(9 citation statements)

References 31 publications

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“…The docking procedure was done by AutoDock 4.2 and the .dlg file was generated. All of the runs were ranked by the maximum number of clusters and the lowest binding energy and were analyzed to find the best conformation of the ligand with key residues in the active site of the protein by Accelrys Discovery Studio 2.5 [25] and PyMOL software [26]. …”

Section: Methodsmentioning

confidence: 99%

“…The pKa for residues of protein were obtained by the PROPKA 3.1 web server to determined which residue was more possible to embrace nonstandard ionization states [28]. The key crystallographic water molecules in the active site were kept [25]. The GROMOS96 54a7 force field and the simple point charges (SPC) water model were used to create protein topology parameters.…”

Section: Methodsmentioning

confidence: 99%

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Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation

2017

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BackgroundHeat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy.MethodsIn the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The leave-one out (LOO) cross-validation and Y-randomization tests were performed to models’ validation. The new ligands were monitored by applicability domain. Molecular docking studies were also conducted to evaluate the mode of interaction of these compounds with Hsp90. Identification of the likely pathways into the active site pocket and the involved residues were performed by CAVAER 3.0.1 software. According to QSAR models and docking analysis, three new compounds were predicted. 50 ns molecular dynamic simulation was performed for the strongest synthesized compound and the best predicted compound in terms of binding energy and interactions between ligand and protein.ResultsThe made models showed the significance of size, shape, symmetry, and branching of molecules in inhibitory activities of Hsp90. Docking studies indicated that two hydroxyl groups in the resorcinol ring were important in interacting with Asp93 and the orientation of these groups was related to substitution of different R1 groups. Comparing of molecular dynamic simulation (MDs) results shows that new compound perched in active site with lower binding energy than the best synthesized compound.ConclusionThe QSAR and docking analyses shown to be beneficial tools in the proposal of anti-cancer activities and a leader to the synthesis of new Hsp90 inhibitors based 3,4-isoxazolediamide. The MDs confirmed that predicted ligand is steady in the Hsp90 active sites.Graphical Abstract

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation

2017

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“…Each docking job was carried out by 100 runs. All other parameters and the docking validation were performed using previously published methods ( 22 ).…”

Section: Methodsmentioning

confidence: 99%

Novel N-substituted indole hydrazones as potential antiplatelet agents: synthesis, biological evaluations, and molecular docking studies

et al. 2022

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Background and purpose: Antiplatelet agents can diminish the chance of coronary heart diseases due to the prevention of unusual clotting in the arteries by inhibiting platelet aggregation and avoiding the formation of a blood clot. This mechanism can help to prevent ischemic stroke likewise. To improve the activity of these drugs and reduce their side effects, further studies are required. Experimental approach: Based on the previous studies representing the promising antiplatelet activity of indole hydrazones, a series of their homologs containing twenty-one compounds were prepared in two steps. First, alkylation reaction on the nitrogen of the indole ring, and second, chiff base formation by condensation of a primary amine and N-substituted indole-3 carbaldehyde. Consequently, their platelet anti-aggregation activity was evaluated based on the Born turbidimetric method. Findings/Results: Most of the compounds exhibited noticeable activity against platelet aggregation induced by arachidonic acid. Amongst them, two compounds 2e and 2f showed higher activity with IC 50 values that made comparable to indomethacin and acetylsalicylic acid as standard drugs and had no toxicity on platelets. Conclusion and implications: The synthesized compounds exhibited promising activity against arachidonic acid-induced aggregation; however, none of them showed noticeable antiplatelet activity induced by adenosine di-phosphate. Chemical structure comparison of the prepared derivatives indicated the existence of a lipophilic medium-sized group on the phenyl ring increased their activity. In addition, the docking studies confirmed this hydrophobic interaction in the lipophilic pocket of cyclooxygenase-1 enzyme suggesting that hydrophobicity of this region plays a pivotal role in the anti-platelet activity of these compounds. To prove this finding, the enzymatic evaluation with the target enzyme is required.

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“…However, these target proteins encompass many elevated or transmuted carcinogenic proteins, including p53 and hTERT, some of which are associated with cancer characteristics [ 48 , 49 ]. These customer proteins in tumour generation, growth, invasion, and metastasis make HSP90 an appealing therapeutic cancer target [ 50 , 51 ]. The overexpression of HSP90 has been observed in patients with cancer, and it has been observed that HSP90 triggers the unstable harmful kinase functions, which enhance carcinogenesis [ 52 , 53 ].…”

Section: Overview Of Some Cancer Therapeutic Targets For Drug Discoverymentioning

confidence: 99%

Heat Shock Protein 90 (HSP90) Inhibitors as Anticancer Medicines: A Review on the Computer-Aided Drug Discovery Approaches over the Past Five Years

Magwenyane

Ugbaja

Amoako

et al. 2022

Computational and Mathematical Methods in Medicine

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Cancer is a disease caused by the uncontrolled, abnormal growth of cells in different anatomic sites. In 2018, it was predicted that the worldwide cancer burden would rise to 18.1 million new cases and 9.6 million deaths. Anticancer compounds, often known as chemotherapeutic medicines, have gained much interest in recent cancer research. These medicines work through various biological processes in targeting cells at various stages of the cell’s life cycle. One of the most significant roadblocks to developing anticancer drugs is that traditional chemotherapy affects normal cells and cancer cells, resulting in substantial side effects. Recently, advancements in new drug development methodologies and the prediction of the targeted interatomic and intermolecular ligand interaction sites have been beneficial. This has prompted further research into developing and discovering novel chemical species as preferred therapeutic compounds against specific cancer types. Identifying new drug molecules with high selectivity and specificity for cancer is a prerequisite in the treatment and management of the disease. The overexpression of HSP90 occurs in patients with cancer, and the HSP90 triggers unstable harmful kinase functions, which enhance carcinogenesis. Therefore, the development of potent HSP90 inhibitors with high selectivity and specificity becomes very imperative. The activities of HSP90 as chaperones and cochaperones are complex due to the conformational dynamism, and this could be one of the reasons why no HSP90 drugs have made it beyond the clinical trials. Nevertheless, HSP90 modulations appear to be preferred due to the competitive inhibition of the targeted N-terminal adenosine triphosphate pocket. This study, therefore, presents an overview of the various computational models implored in the development of HSP90 inhibitors as anticancer medicines. We hereby suggest an extensive investigation of advanced computational modelling of the three different domains of HSP90 for potent, effective inhibitor design with minimal off-target effects.

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Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking, molecular dynamic simulation and virtual screening

Cited by 15 publications

References 31 publications

Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation

Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation

Novel N-substituted indole hydrazones as potential antiplatelet agents: synthesis, biological evaluations, and molecular docking studies

Heat Shock Protein 90 (HSP90) Inhibitors as Anticancer Medicines: A Review on the Computer-Aided Drug Discovery Approaches over the Past Five Years

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