Identification of Novel Potential VEGFR-2 Inhibitors Using a Combination of Computational Methods for Drug Discovery

Al-Sanea, Mohammad M.; Chilingaryan, Garri; Abelyan, Narek; Sargsyan, A. A.; Hovhannisyan, Sargis; Gasparyan, Hayk; Gevorgyan, Smbat; Albogami, Sarah; Ghoneim, Mohammed M.; Farag, Ahmed Karam; Mohamed, Ahmed A. B.; El-Damasy, Ashraf K.

doi:10.3390/life11101070

Cited by 15 publications

(12 citation statements)

References 41 publications

(44 reference statements)

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“…Newly designed molecules N1/N3/N5/N6/N9 and template molecules were selected for molecular dynamics studies using the AMBER16 software package. 30,31 The complex systems are pretreated before performing the simulation, GAFF forces fields is used for ligand small molecules, 32 and ff14SB force fields are applied to proteins for the construction and assembly of topological files. 33 The TIP3PBOX(Buffer Z10.0 Å) waters model was used to dissolve the solute in an uncapped periodic box of a solvent wall distance from 1.2 nm, and then sodium and chloride ions were added to keep the system electrically neutral.…”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

3D-QSAR, molecular docking and molecular dynamics analysis of pyrazole derivatives as MALT1 inhibitors

Chen,

Li,

Wang

et al. 2023

New J. Chem.

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Section: Molecular Dynamics Simulationmentioning

confidence: 99%

3D-QSAR, molecular docking and molecular dynamics analysis of pyrazole derivatives as MALT1 inhibitors

Chen,

Li,

Wang

et al. 2023

New J. Chem.

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“…However, ramucirumab has been associated with limited efficacy, potentially severe side effects, and high cost [ 10 , 11 ]. Similarly, currently available small molecules have been associated with acquired drug resistance, limited efficacy, compound toxicity, and a wide range of side effects [ 12 ]. Toxicities of VEGFR inhibitors observed in the clinic include hypertension, proteinuria, hypothyroidism, leukoencephalopathy syndrome, and arterial thrombosis, among others [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Comparative biochemical kinase activity analysis identifies rivoceranib as a highly selective VEGFR2 inhibitor

Jang¹,

Strickland²,

Finis³

et al. 2023

Cancer Chemother Pharmacol

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Vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of tumor angiogenesis, is highly expressed across numerous tumor types and has been an attractive target for anti-cancer therapy. However, clinical application of available VEGFR2 inhibitors has been challenged by limited efficacy and a wide range of side effects, potentially due to inadequate selectivity for VEGFR2. Thus, development of potent VEGFR2 inhibitors with improved selectivity is needed. Rivoceranib is an orally administered tyrosine kinase inhibitor that potently and selectively targets VEGFR2. A comparative understanding of the potency and selectivity of rivoceranib and approved inhibitors of VEGFR2 is valuable to inform rationale for therapy selection in the clinic. Here, we performed biochemical analyses of the kinase activity of VEGFR2 and of a panel of 270 kinases to compare rivoceranib to 10 FDA-approved kinase inhibitors (“reference inhibitors”) with known activity against VEGFR2. Rivoceranib demonstrated potency within the range of the reference inhibitors, with a VEGFR2 kinase inhibition IC50 value of 16 nM. However, analysis of residual kinase activity of the panel of 270 kinases showed that rivoceranib displayed greater selectivity for VEGFR2 compared with the reference inhibitors. Differences in selectivity among compounds within the observed range of potency of VEGFR2 kinase inhibition are clinically relevant, as toxicities associated with available VEGFR2 inhibitors are thought to be partly due to their effects against kinases other than VEGFR2. Together, this comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with off-target effects of currently available VEGFR2 inhibitors.

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“…The inhibition of VEGFR‐2 averts the phosphorylation and dimerization processes, resulting in the arrest of angiogenesis. [ 2,3 ]…”

Section: Introductionmentioning

confidence: 99%

Discovery of VEGFR inhibitors through virtual screening and energy assessment

Reang

Sharma

et al. 2023

J Biochem & Molecular Tox

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Vascular endothelial growth factor receptor-2 (VEGFR-2) is crucial in promoting tumor angiogenesis and cancer metastasis. Thus, inhibition of VEGFR-2 has appeared as a good tactic for cancer treatment. To find out novel VEGFR-2 inhibitors, first, the PDB structure of VEGFR-2, 6GQO, was selected based on atomic nonlocal environment assessment (ANOLEA) and PROCHECK assessment.6GQO was then further used for structure-based virtual screening (SBVS) of different molecular databases, including US-FDA approved drugs, US-FDA withdrawn drugs, may bridge, MDPI, and Specs databases using Glide. Based on SBVS, receptor fit, drug-like filters, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of 427877 compounds, the best 22 hits were selected.From the 22 hits, hit 5 complex with 6GQO was put through molecular mechanics/ generalized born surface area (MM/GBSA) study and hERG binding. The MM/GBSA study revealed that hit 5 possesses lesser binding free energy with more inferior stability in the receptor pocket than the reference compound. The VEGFR-2 inhibition assay of hit 5 disclosed an IC 50 of 165.23 nM against VEGFR-2, which can be possibly enhanced through structural modifications.

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Identification of Novel Potential VEGFR-2 Inhibitors Using a Combination of Computational Methods for Drug Discovery

Cited by 15 publications

References 41 publications

3D-QSAR, molecular docking and molecular dynamics analysis of pyrazole derivatives as MALT1 inhibitors

3D-QSAR, molecular docking and molecular dynamics analysis of pyrazole derivatives as MALT1 inhibitors

Comparative biochemical kinase activity analysis identifies rivoceranib as a highly selective VEGFR2 inhibitor

Discovery of VEGFR inhibitors through virtual screening and energy assessment

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