Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity

Zaraei, Seyed–Omar; Alach, Nour N.; Anbar, Hanan S.; El-Gamal, Randa; Tarazi, Hamadeh; Tokatly, Rimas T.; Kalla, Rawan R.; Munther, Mouna A.; Wahba, Marwa M.; Alshihabi, Aya M.; Shehata, Mahmoud K.; Sbenati, Rawan M.; Shahin, Afnan I.; El‐Awady, Raafat; Al‐Tel, Taleb H.; El‐Gamal, Mohammed I.

doi:10.1016/j.ejmech.2022.114434

Cited by 13 publications

(10 citation statements)

References 38 publications

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“…The suggested compounds belong to the class of quinolines and derivatives, and flavonoids, respectively predicted and analyzed by the ClassyFire tool [ 43 ]. These classes of compounds are also reported as inhibitors for certain kinases, such as tyrosine kinases and other protein kinases [ 63 , 64 ]. Additionally, luteolin, a reported histidine kinase inhibitor, also belongs to the flavonoid class [ 33 , 64 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of histidine kinase inhibitors through screening of natural compounds to combat mastitis caused by Streptococcus agalactiae in dairy cattle

Pathak,

Kim

2023

J Biol Eng

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Background Mastitis poses a major threat to dairy farms globally; it results in reduced milk production, increased treatment costs, untimely compromised genetic potential, animal deaths, and economic losses. Streptococcus agalactiae is a highly virulent bacteria that cause mastitis. The administration of antibiotics for the treatment of this infection is not advised due to concerns about the emergence of antibiotic resistance and potential adverse effects on human health. Thus, there is a critical need to identify new therapeutic approaches to combat mastitis. One promising target for the development of antibacterial therapies is the transmembrane histidine kinase of bacteria, which plays a key role in signal transduction pathways, secretion systems, virulence, and antibiotic resistance. Results In this study, we aimed to identify novel natural compounds that can inhibit transmembrane histidine kinase. To achieve this goal, we conducted a virtual screening of 224,205 natural compounds, selecting the top ten based on their lowest binding energy and favorable protein–ligand interactions. Furthermore, molecular docking of eight selected antibiotics and five histidine kinase inhibitors with transmembrane histidine kinase was performed to evaluate the binding energy with respect to top-screened natural compounds. We also analyzed the ADMET properties of these compounds to assess their drug-likeness. The top two compounds (ZINC000085569031 and ZINC000257435291) and top-screened antibiotics (Tetracycline) that demonstrated a strong binding affinity were subjected to molecular dynamics simulations (100 ns), free energy landscape, and binding free energy calculations using the MM-PBSA method. Conclusion Our results suggest that the selected natural compounds have the potential to serve as effective inhibitors of transmembrane histidine kinase and can be utilized for the development of novel antibacterial veterinary medicine for mastitis after further validation through clinical studies.

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Section: Discussionmentioning

confidence: 99%

Identification of histidine kinase inhibitors through screening of natural compounds to combat mastitis caused by Streptococcus agalactiae in dairy cattle

Pathak,

Kim

2023

J Biol Eng

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“…We chose the 3-aminoquinoline core as an appropriate probe. The quinoline scaffold is well established in medicinal chemistry and kinase inhibitor design ( Musiol, 2017 ; Zhou et al, 2020 ; Zaraei et al, 2022 ; Kim et al, 2023 ). Structurally diverse fragments (94 structures) were used as building blocks ( Supplementary Figure S9 ).…”

Section: Resultsmentioning

confidence: 99%

Quantum-assisted fragment-based automated structure generator (QFASG) for small molecule design: an in vitro study

Evteev,

Ivanenkov,

Semenov

et al. 2024

Front. Chem.

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Introduction: The significance of automated drug design using virtual generative models has steadily grown in recent years. While deep learning-driven solutions have received growing attention, only a few modern AI-assisted generative chemistry platforms have demonstrated the ability to produce valuable structures. At the same time, virtual fragment-based drug design, which was previously less popular due to the high computational costs, has become more attractive with the development of new chemoinformatic techniques and powerful computing technologies.Methods: We developed Quantum-assisted Fragment-based Automated Structure Generator (QFASG), a fully automated algorithm designed to construct ligands for a target protein using a library of molecular fragments. QFASG was applied to generating new structures of CAMKK2 and ATM inhibitors.Results: New low-micromolar inhibitors of CAMKK2 and ATM were designed using the algorithm.Discussion: These findings highlight the algorithm’s potential in designing primary hits for further optimization and showcase the capabilities of QFASG as an effective tool in this field.

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“…Moreover, the length of the urea spacer facilitated the molecule to occupy a large area within the target enzyme. This increased the affinity resulting in a strong anticancer activity [70] …”

Section: Quinoline‐based Raf Kinase Inhibitorsmentioning

confidence: 99%

Novel Quinoline‐Based RAF Inhibitors: A Comprehensive Review on Synthesis, SAR and Molecular Docking Studies

Sahu,

Mishra,

Wal

et al. 2024

ChemistrySelect

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The RAF (rapidly accelerated fibrosarcoma) kinases play critical roles in a variety of different cellular processes, including the advancement of the cell cycle, the proliferation of cells, the metabolism of cells, cell migration, and the differentiation of cells. RAF kinase was thus established as an important target for the management of cancer disease. RAF inhibitors have elicited remarkable responses and enhanced survival rates in patients with BRAF‐V600E/K melanoma, but their efficacy is restricted by resistance as a result of mutations in RAF, presenting challenges in the identification of novel RAF inhibitors. This has resulted in the development of two generations of RAF inhibitors. In the past years, a variety of heterocyclic scaffolds that are capable of inhibiting RAF activity have been discovered. Quinoline, a molecule with a fused benzene ring and N‐heterocyclic pyridine, is a prime template for designing a variety of new anticancer drugs. In the last few years, quinoline derivative has been studied for their capability to inhibit RAF kinases. In this review, we have summarized synthesis, biological study, and molecular docking studies of substituted quinoline derivatives, which have shown potent anticancer activity by inhibiting the RAF kinases. The present review would help medicinal chemists streamline and guide their efforts toward developing novel quinoline‐based RAF inhibitors, which will be beneficial for drug development.

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Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity

Cited by 13 publications

References 38 publications

Identification of histidine kinase inhibitors through screening of natural compounds to combat mastitis caused by Streptococcus agalactiae in dairy cattle

Identification of histidine kinase inhibitors through screening of natural compounds to combat mastitis caused by Streptococcus agalactiae in dairy cattle

Quantum-assisted fragment-based automated structure generator (QFASG) for small molecule design: an in vitro study

Novel Quinoline‐Based RAF Inhibitors: A Comprehensive Review on Synthesis, SAR and Molecular Docking Studies

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