Fibroblast growth factor receptor (FGFR) inhibitors as anticancer agents: 3D-QSAR, molecular docking and dynamics simulation studies of 1, 6-naphthyridines and pyridopyrimidines

Modh, Dharti; Modi, Siddharth J.; Deokar, Hemant; Yadav, Savita S; Kulkarni, Vithal M.

doi:10.1080/07391102.2022.2053206

Cited by 5 publications

(4 citation statements)

References 25 publications

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“…NeoB is a complex aminoglycoside compound composed of four moieties, including d ‐neosamine, 2‐deoxystreptamine, d ‐ribose sugar, and l ‐neosamine, and contains the largest number of free amino groups (six). The molecular docking analysis revealed that it formed hydrogen bond interactions with several amino acid residues of FGFR, including Gly474 and Leu473 via d ‐neosamine, Ala553 via 2‐deoxystreptamine, Arg616, and Glu475 via d ‐ribose, and Asp630 (DFG motif), Asn617, and Glu475 via l ‐neosamine 54 . These results suggest that NeoB has the potential to serve as a promising lead compound for the development of FGFR‐targeting therapeutics.…”

Section: Resultsmentioning

confidence: 93%

“…The results showed that pazopanib exhibited 89% hydrogen bond interactions with residue Ala554 through its sulfonamide group and 97% H‐bond interaction through its pyrimidine ring. NeoB formed 41% water bridging interaction with residue Asp630 in the DGF motif of FGFR via its d ‐ribose sugar 54,58 . DPGA exhibited 46% hydrogen bond interactions with the Glu560 residue of receptor through its phosphate moiety and 50% H‐bond interaction with Asn557 via its galacturonic acid moiety 59 .…”

Section: Resultsmentioning

confidence: 99%

“…The molecular docking analysis revealed that it formed hydrogen bond interactions with several amino acid residues of FGFR, including Gly474 and Leu473 via Dneosamine, Ala553 via 2-deoxystreptamine, Arg616, and Glu475 via D-ribose, and Asp630 (DFG motif), Asn617, and Glu475 via L-neosamine. 54 These results suggest that NeoB has the potential to serve as a promising lead compound for the development of FGFR-targeting therapeutics. The ligand DPGA exhibited two hydrogen bond interactions with Asn557 and Arg616 through its hydrogen phosphate group.…”

Section: Molecular Dockingmentioning

confidence: 93%

“…NeoB formed 41% water bridging interaction with residue Asp630 in the DGF motif of FGFR via its D-ribose sugar. 54,58 DPGA exhibited 46% hydrogen bond interactions with the Glu560 residue of receptor through its phosphate moiety and 50% H-bond interaction with Asn557 via its galacturonic acid moiety. 59 Epi demonstrated hydrogen bond interaction with Ala553 amino acid residue through its hydroxyl and keto groups present in the anthraquinone ring.…”

Section: Protein−ligand Interactionmentioning

confidence: 99%

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From nature to cancer therapy: Evaluating the Streptomyces clavuligerus secondary metabolites for potential protein kinase inhibitors

Saini,

Kumari,

Singh

et al. 2023

J of Cellular Biochemistry

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The study aimed to evaluate the antioxidant, protein kinase inhibitory (PKIs) potential, cytotoxicity activity of Streptomyces clavuligerus extract. DPPH assay revealed a robust free radical scavenging capacity (IC50 28.90 ± 0.24 µg/mL) of organic extract with a maximum inhibition percentage of 61 ± 1.04%. PKIs assay revealed the formation of a whitish bald zone by S. clavuligerus extracts which indicates the presence of PKIs. The cytotoxicity activity of organic fraction of extract through Sulforhodamine B assay on MCF‐7, Hop‐62, SiHa, and PC‐3 cell lines demonstrated the lowest GI50 value against the MCF‐7 cell line followed by the PC‐3 cell line, showing potent growth inhibitory potential against human breast cancer and human prostate cancer cell line. HR‐LCMS analysis identified multiple secondary metabolites from the organic and aqueous extracts of S. clavuligerus when incubated at 30°C under 200 rpm for 3 days. All the secondary metabolites were elucidated for their potential to inhibit RTKs by molecular docking, molecular dynamic simulation, MM/GBSA calculations, and free energy approach. It revealed the superior inhibitory potential of epirubicin (Epi) and dodecaprenyl phosphate‐galacturonic acid (DPGA) against fibroblast growth factors receptor (FGFR). Epi also exhibited excellent inhibitory activity against the platelet‐derived growth factor receptor (PDGFR), while DPGA effectively inhibited the vascular endothelial growth factor receptor. Additionally, the presence Epi in S. clavuligerus extract was validated through the HPLC technique. Thus, our findings highlight a superior inhibitory potential of Epi against FGFR and PDGFR RTKs than the FDA‐approved drug.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 93%