Discovery of New Coumarin-Based Lead with Potential Anticancer, CDK4 Inhibition and Selective Radiotheranostic Effect: Synthesis, 2D &amp; 3D QSAR, Molecular Dynamics, In Vitro Cytotoxicity, Radioiodination, and Biodistribution Studies

Sarhan, Mona O.; El-Karim, Somaia S. Abd; Anwar, Manal M.; Gouda, Raghda H; Zaghary, Wafaa A.; Khedr, Mohammed A.

doi:10.3390/molecules26082273

Cited by 18 publications

(15 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to VS, QSAR studies are a valuable tool for ligand-based hit compound optimization. This approach has been employed in radiotracer development for multiple targets, including dopamine receptors [ 135 , 136 , 137 , 138 , 139 , 140 ], serotonin receptors [ 141 ], sigma receptors [ 142 , 143 ], beta-amyloid fibrils [ 4 , 144 , 145 ], and cancer-related kinases or receptors [ 146 , 147 , 148 , 149 ]. A QSAR model that is built to investigate ligand fragments that contribute to the binding affinities for multiple proteins, such as target and off-target proteins, can be used to predict the binding affinity for a protein of interest as well as selectivity versus off-target binding.…”

Section: Hit Compound Optimizationmentioning

confidence: 99%

Computational Chemistry for the Identification of Lead Compounds for Radiotracer Development

et al. 2023

View full text Add to dashboard Cite

The use of computer-aided drug design (CADD) for the identification of lead compounds in radiotracer development is steadily increasing. Traditional CADD methods, such as structure-based and ligand-based virtual screening and optimization, have been successfully utilized in many drug discovery programs and are highlighted throughout this review. First, we discuss the use of virtual screening for hit identification at the beginning of drug discovery programs. This is followed by an analysis of how the hits derived from virtual screening can be filtered and culled to highly probable candidates to test in in vitro assays. We then illustrate how CADD can be used to optimize the potency of experimentally validated hit compounds from virtual screening for use in positron emission tomography (PET). Finally, we conclude with a survey of the newest techniques in CADD employing machine learning (ML).

show abstract

Section: Hit Compound Optimizationmentioning

confidence: 99%

Computational Chemistry for the Identification of Lead Compounds for Radiotracer Development

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Sarhan and coworkers [ 34 ] used docking differently, as a method for validating their findings. They developed an inhibitor of cyclin-dependent kinase 4 (CDK4), which can be used for the treatment of various neoplasms due to the overexpression of this kinase in multiple tumor cells.…”

Section: Resultsmentioning

confidence: 99%

Radionuclide Delivery Strategies in Tumor Treatment: A Systematic Review

Poletto

Cecchin²,

Bartoletti³

et al. 2022

CIMB

View full text Add to dashboard Cite

The aim of this review was to assess recent progress in targeted radionuclide tumor therapy, focusing on the best delivery strategies. A literature search was conducted in PubMed, Web of Science, and Scopus using the terms “radionuclides”, “liposomes”, “avidin–biotin interaction”, “theranostic”, and “molecular docking”. The 10 year filter was applied, except for the avidin–biotin interaction. Data were retrieved from both preclinical and clinical settings. Three targeting strategies were considered: pretargeting, liposomes, and ligands. Pretargeting can be achieved by exploiting the avidin–biotin interaction. This strategy seems very promising, although it has been investigated mainly in resectable tumors. Radiolabeled liposomes have attracted new interest as probes to identify the most suitable patients for treatment with liposomal formulations of common chemotherapeutics. The use of ligands for the delivery of radiotherapeutics to a specific target is still the most appealing strategy for treating tumors. The most appropriate ligand can be identified by virtually simulating its interaction with the receptor. All strategies showed great potential for use in targeted radionuclide therapy, but they also have numerous drawbacks. The most promising option is probably the one based on the use of new ligands.

show abstract

“…Coumarin derivatives exhibit various biological activities, such as anticancer (Ahmed et al, 2020; Alshabanah et al, 2022; Channar et al, 2019; Sarhan et al, 2021), antimicrobial (Hu et al, 2021; Liu et al, 2020), anti‐HIV (Xu et al, 2021), anti‐inflammatory (Di Stasi, 2021; Emam et al, 2021), antioxidant (Antonijević et al, 2021), anticonvulsant (El‐Ansary et al, 2016), antithrombotic (Gao et al, 2021), and antidepressant (Wang et al, 2021) activities.…”

Section: Introductionmentioning

confidence: 99%

Coumarin derivatives with potential anticancer and antibacterial activity: Design, synthesis, VEGFR‐2 and DNA gyrase inhibition, and in silico studies

Emam

Hassan

Osman

et al. 2023

Drug Development Research

View full text Add to dashboard Cite

A series of coumarin derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Compound 3e exhibited significant antiproliferative activity and was further evaluated at five doses at the National Cancer Institute. It effectively inhibited vascular endothelial growth factor receptor-2 (VEGFR-2) with an IC 50 value of 0.082 ± 0.004 µM compared with sorafenib. While compound 3e significantly downregulated total VEGFR-2 and its phosphorylation, it markedly reduced the HUVEC's migratory potential, resulting in a significant disruption in wound healing. Furthermore, compound 3e caused a 22.51-fold increment in total apoptotic level in leukemia cell line HL-60(TB) and a 6.91-fold increase in the caspase-3 level. Compound 3e also caused cell cycle arrest, mostly at the G1/S phase. Antibacterial activity was evaluated against Gram-positive and Gram-negative bacterial strains. Compound 3b was the most active derivative, with the same minimum inhibitory concentration and minimum bactericidal concentration value of 128 μg/mL against K. pneumonia and high stability in mammalian plasma. Moreover, compounds 3b and 3f inhibited Gram-negative DNA gyrase with IC 50 = 0.73 ± 0.05 and 1.13 ± 0.07 µM, respectively, compared to novobiocin with an IC 50 value of 0.17 ± 0.02 µM. The binding affinity and pattern of derivative 3e toward the VEGFR-2 active site and compounds 3a-c and 3f in the DNA gyrase active site were evaluated using molecular modeling. Overall, ADME studies of the synthesized coumarin derivatives displayed promising pharmacokinetic properties.

show abstract

Discovery of New Coumarin-Based Lead with Potential Anticancer, CDK4 Inhibition and Selective Radiotheranostic Effect: Synthesis, 2D & 3D QSAR, Molecular Dynamics, In Vitro Cytotoxicity, Radioiodination, and Biodistribution Studies

Cited by 18 publications

References 63 publications

Computational Chemistry for the Identification of Lead Compounds for Radiotracer Development

Computational Chemistry for the Identification of Lead Compounds for Radiotracer Development

Radionuclide Delivery Strategies in Tumor Treatment: A Systematic Review

Coumarin derivatives with potential anticancer and antibacterial activity: Design, synthesis, VEGFR‐2 and DNA gyrase inhibition, and in silico studies

Contact Info

Product

Resources

About