Discovery of new pyrimidine-5-carbonitrile derivatives as anticancer agents targeting EGFR<sup>WT</sup>and EGFR<sup>T790M</sup>

Nasser, Ahmed A.; Eissa, Ibrahim H.; Oun, Mohamed R.; El‐Zahabi, Mohamed Ayman; Taghour, Mohammed S; Belal, Amany; Saleh, Abdulrahman M.; Mehany, Ahmed B. M.; Luesch, Hendrik; Mostafa, Ahmad E.; Afifi, Wael M.; Rocca, James R.; Mahdy, Hazem A.

doi:10.1039/d0ob01557a

Cited by 95 publications

(69 citation statements)

References 96 publications

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“…Table 1 demonstrates the molecular properties of the similar candidates as well as SAM. 3 Hydrogen bond acceptors, 4 Hydrogen bond donors, 5 Molecular fractional polar surface area.…”

Section: Molecular Similarity Against Sammentioning

confidence: 99%

“…Computer-assisted (based or aided) drug design is a well-established branch of drug design that covers various in silico computational and theoretical approaches. These approaches are essential contributors to the development of new bioactive agents [2][3][4][5][6][7][8]. Computer-assisted drug design has been applied in drug discovery [9][10][11], computational chemistry [12,13], toxicity prediction [14][15][16], ADMET assessment [17][18][19], molecular modeling [20], molecular design [21,22], and rational drug design [23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

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In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

et al. 2021

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In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.

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“…Table 1 demonstrates the molecular properties of the similar candidates as well as SAM. 3 Hydrogen bond acceptors, 4 Hydrogen bond donors, 5 Molecular fractional polar surface area.…”

Section: Molecular Similarity Against Sammentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

et al. 2021

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“…en, the protein structure was protonated and the hydrogen atoms were hidden. Next, the energy was minimized and the binding pocket of the protein was defined [46][47][48].…”

Section: Molecular Dockingmentioning

confidence: 99%

In Vitro and In Silico Cytotoxic and Antibacterial Activities of a Diterpene from Cousinia alata Schrenk

Zhanzhaxina

Suleimen

Metwaly

et al. 2021

Journal of Chemistry

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A biologically guided isolation of secondary metabolites from Cousinia alata Schrenk wild plant growing in Akmola region, Kazakhstan, led to the isolation of the bioactive diterpene grindelic acid (1). Six flavonoids were also isolated and identified as retusine (2), pachipodol (3), jaranol (4), penduletin (5), casticin (6), and 5, 7, 3′-trihydroxy-3, 4′-dimethoxyflavone (7). Penduletin (5) showed moderate cytotoxic activity assay. Grindelic acid exhibited promising cytotoxic activity against the Artemia salina nauplii and antibacterial activity against Staphylococcus aureus, Bacillus cereus, and Salmonella enteritidis. The presence of the essential pharmacophoric features of histone deacetylase (HDAC) inhibitors in the structure of grindelic acid encouraged us to run a molecular docking study against the HDAC enzyme to understand its mechanism of action on a molecular level. Grindelic acid showed a binding mode of interaction similar to that of the cocrystallized ligand and exhibited good binding affinity against HDAC with the binding free energy of −18.70 kcal/mol. The structures of isolated compounds were determined by MS, 1D, and 2D NMR spectroscopy methods. Compounds (1–7) were isolated for the first time from Cousinia genus.

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“…The docking studies were performed utilising MOE.14 software as described in Supplementary Data 57 , 100 , 101 . The final figures were visualised using Discovery studio 4.0 102 .…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers

Alanazi

Eissa

Alsaif

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC 50 of 3.2 nM very close to positive control sorafenib (IC 50 = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC 50 of 7.7 and 4.5 µM in comparison to sorafenib (IC 50 = 3.51 and 2.17 µM). In addition, compounds 28 , 30f , 30i , and 31b exhibited excellent VEGFR-2 inhibition activities (IC 50 range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a . Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles

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Discovery of new pyrimidine-5-carbonitrile derivatives as anticancer agents targeting EGFR^WTand EGFR^T790M

Abstract: A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR). These compounds were synthesized and evaluated for their in...

Cited by 95 publications

References 96 publications

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

In Vitro and In Silico Cytotoxic and Antibacterial Activities of a Diterpene from Cousinia alata Schrenk

Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers

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Discovery of new pyrimidine-5-carbonitrile derivatives as anticancer agents targeting EGFRWTand EGFRT790M

Abstract: A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR). These compounds were synthesized and evaluated for their in...

Cited by 95 publications

References 96 publications

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

In Vitro and In Silico Cytotoxic and Antibacterial Activities of a Diterpene from Cousinia alata Schrenk

Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers

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Discovery of new pyrimidine-5-carbonitrile derivatives as anticancer agents targeting EGFR^WTand EGFR^T790M