Structure-based pharmacophore mapping and virtual screening of natural products to identify polypharmacological inhibitor against c-MET/EGFR/VEGFR-2

Varma, Diksha A; Singh, Mrityunjay; Wakode, Sharad; Dinesh, N E; Vinaik, Simran; Asthana, Shailendra; Tiwari, Manisha

doi:10.1080/07391102.2022.2042388

Cited by 11 publications

(3 citation statements)

References 57 publications

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“…AUTOGRID 4.0 (https:// autodock.scripps.edu/download-autodock4/) was employed to build a 60 9 60 9 60 points grid map covering the whole protein, with spacing of 0.250 A and centered around the residues of reported binding site T57, T59, V61, R63, R96, Q116, A251, A252, F266, F267, S268, I271, R273, I275, L295, F300, L328, I341, L343, T369, L371, T380, F383, K385, R386, L387, N417 and E418 of the protein. The Lamarckian genetic algorithm, using a scoring function based on the AMBER force field [41][42][43], was used for conformational sampling of each compound. For each docking simulation, 200 runs were carried out with 300 random individuals in first population, 2.5 9 105 energy evaluations and 2.7 9 105 numbers of generations.…”

Section: Interaction Study With Cholesterol Through Molecular Dockingmentioning

confidence: 99%

Elevated glycosylation of CD36 in platelets is a risk factor for oxLDL‐mediated platelet activation in type 2 diabetes

Agarwal,

Saha,

Ghosh

et al. 2023

The FEBS Journal

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Platelet activation and related cardiovascular complications are the hallmarks of type 2 diabetes (T2D). We investigated the mechanism of platelet activation in T2D using mass spectrometry‐ based identification of differentially expressed platelet proteins with a focus on glycosylated forms. Glycosylation is considered one of the common post‐translational modifications in T2D, and N/O‐linked glycosylation of glycoproteins/integrins is known to play crucial roles in platelet activation. Our platelet proteome data revealed elevated levels of glycoproteins GPIbα, GPIIbIIIa, GPIV (CD36), GPV and integrins in T2D patients. T2D platelets had elevated N‐linked glycosylation of CD36 at asparagine (Asn)408,417. Enrichment analysis revealed a close association of glycosylated CD36 with thrombospondin‐1, fibrinogen and SERPINA1 in T2D platelets. The glycosylation of CD36 has previously been reported to increase cellular uptake of long‐chain fatty acids. Our in silico molecular docking data also showed a favourable binding of cholesterol with glycosylated Asn417 CD36 as compared to the non‐glycosylated form. We further investigated the CD36:LDL cholesterol axis in T2D. Elevated levels of oxidized‐LDL (oxLDL) were found to cause significant platelet activation via CD36‐mediated stimulation of Lyn‐JNK signaling. Sulfo‐n‐succinimidyl oleate (SSO), an inhibitor of CD36, effectively inhibited oxLDL‐mediated platelet activation and adhesion in vitro. Our study suggests increased glycosylation of CD36 in T2D platelets as a potential route for oxLDL‐mediated platelet activation. The oxLDL:CD36 axis may thus be exploited as a prospective target to develop therapeutics against thrombosis in T2D.

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Section: Interaction Study With Cholesterol Through Molecular Dockingmentioning

confidence: 99%

Elevated glycosylation of CD36 in platelets is a risk factor for oxLDL‐mediated platelet activation in type 2 diabetes

Agarwal,

Saha,

Ghosh

et al. 2023

The FEBS Journal

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“…The polypharmacology of the flavonol "cediodarin" against three RTKs was performed by structure-based pharmacophore mapping and virtual screening of natural products library of compounds. Good affinity results were found for cediodarin against c-MET, EGFR, and VEGFR-2 [96]. High throughput virtual screening for EGFR inhibitors 400,000 compound library of tyrosine kinase inhibitors from ChemBioBase Indenopyrazole framework was reported as cyclin-dependent kinase inhibitor.…”

Section: Vascular Endothelial Growth Factor Receptor-2 (Vegfr-2)mentioning

confidence: 99%

“…The polypharmacology of the flavonol “cediodarin” against three RTKs was performed by structure-based pharmacophore mapping and virtual screening of natural products library of compounds. Good affinity results were found for cediodarin against c-MET, EGFR, and VEGFR-2 [ 96 ].…”

Section: Growth Factor Pathwaysmentioning

confidence: 99%

Target-Based Small Molecule Drug Discovery for Colorectal Cancer: A Review of Molecular Pathways and In Silico Studies

et al. 2022

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Colorectal cancer is one of the most prevalent cancer types. Although there have been breakthroughs in its treatments, a better understanding of the molecular mechanisms and genetic involvement in colorectal cancer will have a substantial role in producing novel and targeted treatments with better safety profiles. In this review, the main molecular pathways and driver genes that are responsible for initiating and propagating the cascade of signaling molecules reaching carcinoma and the aggressive metastatic stages of colorectal cancer were presented. Protein kinases involved in colorectal cancer, as much as other cancers, have seen much focus and committed efforts due to their crucial role in subsidizing, inhibiting, or changing the disease course. Moreover, notable improvements in colorectal cancer treatments with in silico studies and the enhanced selectivity on specific macromolecular targets were discussed. Besides, the selective multi-target agents have been made easier by employing in silico methods in molecular de novo synthesis or target identification and drug repurposing.

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Targeting Intrinsically Disordered Proteins (IDPs) in Drug Discovery

Vemulapalli

2024

Computational Methods for Rational Drug Design

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Structure-based pharmacophore mapping and virtual screening of natural products to identify polypharmacological inhibitor against c-MET/EGFR/VEGFR-2

Cited by 11 publications

References 57 publications

Elevated glycosylation of CD36 in platelets is a risk factor for oxLDL‐mediated platelet activation in type 2 diabetes

Elevated glycosylation of CD36 in platelets is a risk factor for oxLDL‐mediated platelet activation in type 2 diabetes

Target-Based Small Molecule Drug Discovery for Colorectal Cancer: A Review of Molecular Pathways and In Silico Studies

Targeting Intrinsically Disordered Proteins (IDPs) in Drug Discovery

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