Synthesis, evaluation, molecular dynamics simulation and targets identification of novel pyrazole-containing imide derivatives

Cai, Wen-Xi; Wu, Jingwei; Sun, Ying-Zhan; Liu, Ailin; Wang, Run‐Ling; Ma, Ying; Wang, Shuqing; Dong, Wen‐Kui

doi:10.1080/07391102.2020.1745284

Cited by 7 publications

(4 citation statements)

References 54 publications

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“…Cai et al synthesised new pyrazole-containing imide derivatives ( Figure 5(q) ) and assessed them using molecular dynamic simulation [ 156 ]. The HSP90 was suggested as the probable drug target of these compounds with the assistance of pharmacophore and molecular docking.…”

Section: Molecular Reactivity Allosteric Dynamics and Allosteric Designmentioning

confidence: 99%

“…The HSP90 was suggested as the probable drug target of these compounds with the assistance of pharmacophore and molecular docking. The stability of these compounds was evaluated by molecular dynamics [ 156 ]. Magwenyane et al studied the structural and molecular insight into the remedial properties of radicicol (RD) and NVP-YUA922 (NVP) ( Figure 6 ) by inhibition of cancer using DFT, molecular docking, and MD to understand the HSP90 N-terminal dynamics [ 63 ].…”

Section: Molecular Reactivity Allosteric Dynamics and Allosteric Designmentioning

confidence: 99%

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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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Section: Molecular Reactivity Allosteric Dynamics and Allosteric Designmentioning

confidence: 99%

Section: Molecular Reactivity Allosteric Dynamics and Allosteric Designmentioning

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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“…In silico based studies have been conducted for evaluating the efficacy of several pyrazole derivatives for assessing different types of biological properties, including anticancer activity [ 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. In the present study, using molecular docking and molecular dynamic (MD) simulation, a total of 63 pyrazole derivatives were computationally investigated for assessing the modulatory or inhibitory effects against the cited protein targets linked to diverse cancer types.…”

Section: Introductionmentioning

confidence: 99%

In Silico Identification of Promising New Pyrazole Derivative-Based Small Molecules for Modulating CRMP2, C-RAF, CYP17, VEGFR, C-KIT, and HDAC—Application towards Cancer Therapeutics

Bennani

Karrouchi

Doudach

et al. 2022

CIMB

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Despite continual efforts being made with multiple clinical studies and deploying cutting-edge diagnostic tools and technologies, the discovery of new cancer therapies remains of severe worldwide concern. Multiple drug resistance has also emerged in several cancer cell types, leaving them unresponsive to the many cancer treatments. Such a condition always prompts the development of next-generation cancer therapies that have a better chance of inhibiting selective target macromolecules with less toxicity. Therefore, in the present study, extensive computational approaches were implemented combining molecular docking and dynamic simulation studies for identifying potent pyrazole-based inhibitors or modulators for CRMP2, C-RAF, CYP17, c-KIT, VEGFR, and HDAC proteins. All of these proteins are in some way linked to the development of numerous forms of cancer, including breast, liver, prostate, kidney, and stomach cancers. In order to identify potential compounds, 63 in-house synthesized pyrazole-derivative compounds were docked with each selected protein. In addition, single or multiple standard drug compounds of each protein were also considered for docking analyses and their results used for comparison purposes. Afterward, based on the binding affinity and interaction profile of pyrazole compounds of each protein, potentially strong compounds were filtered out and further subjected to 1000 ns MD simulation analyses. Analyzing parameters such as RMSD, RMSF, RoG and protein–ligand contact maps were derived from trajectories of simulated protein–ligand complexes. All these parameters turned out to be satisfactory and within the acceptable range to support the structural integrity and interaction stability of the protein–ligand complexes in dynamic state. Comprehensive computational analyses suggested that a few identified pyrazole compounds, such as M33, M36, M72, and M76, could be potential inhibitors or modulators for HDAC, C-RAF, CYP72 and VEGFR proteins, respectively. Another pyrazole compound, M74, turned out to be a very promising dual inhibitor/modulator for CRMP2 and c-KIT proteins. However, more extensive study may be required for further optimization of the selected chemical framework of pyrazole derivatives to yield improved inhibitory activity against each studied protein receptor.

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“…In this work, we used the computational approach called reverse docking because it has been demonstrated to be efficient and cost‐effective in target identification. PharmMapper was chosen as in silico target prediction tools [31–33]. To validate the main targets found, docking studies were performed on two proteins related to cancer.…”

Section: Introductionmentioning

confidence: 99%

Convergent synthesis, drug target prediction, and docking studies of new 2,6,9‐trisubstituted purine derivatives

Villegas

Satheeshkumar

Ballesteros-Casallas

et al. 2021

Journal of Heterocyclic Chem

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A set of new 2,6,9‐trisubstituted purine derivatives were designed and synthesized from 6‐chloro‐2‐fluoro‐9‐alkyl‐9H‐purine as the key starting material. These purines were synthesized via a multistep protocol and finally subjected to SNAr with various aminopiperidinyl salts. The structures of these compounds were established by substantiating them through spectral techniques like FT‐IR, 1H‐NMR, 13C‐NMR, and 19F‐NMR. In addition, for two purine derivatives, a reverse screening strategy based on ligand similarity (PharmMapper web server) resulted in a set of predicted protein target candidates. Interestingly, for both purines, the main potential target candidates belonged to key proteins involved within signaling pathways that are related to proliferation or survival of cancer cells. These proteins correspond mainly to enzymes and specifically kinases. To check if our purines could be ligands for two kinases involved in cancer, docking studies were performed. The results indicated that these purines fitted in the same cavity of crystalized inhibitors. Therefore, in this work we are developed new purine derivatives that could be good inhibitors of some kinases.

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Synthesis, evaluation, molecular dynamics simulation and targets identification of novel pyrazole-containing imide derivatives

Cited by 7 publications

References 54 publications

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

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

In Silico Identification of Promising New Pyrazole Derivative-Based Small Molecules for Modulating CRMP2, C-RAF, CYP17, VEGFR, C-KIT, and HDAC—Application towards Cancer Therapeutics

Convergent synthesis, drug target prediction, and docking studies of new 2,6,9‐trisubstituted purine derivatives

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