Computational Investigation of 1, 3, 4 Oxadiazole Derivatives as Lead Inhibitors of VEGFR 2 in Comparison with EGFR: Density Functional Theory, Molecular Docking and Molecular Dynamics Simulation Studies

Abstract

Vascular endothelial growth factor (VEGF) is an angiogenic factor involved in tumor growth and metastasis. Gremlin has been proposed as a novel therapeutic pathway for the treatment of renal inflammatory diseases, acting via VEGFR 2 receptor. To date, most FDA-approved tyrosine kinase (TK) inhibitors have been reported as dual inhibitors of EGFR and VEGFR 2. The aim of the present study was to find the potent and selective inhibitor of VEGFR 2 specifically for the treatment of renal cancer. Fourteen previously identified anti-inflammatory compounds i.e., 1, 3, 4 oxadiazoles derivatives by our own group were selected for their anti-cancer potential, targeting the tyrosine kinase (TK) domain of VEGFR2 and EGFR. A detailed virtual screening-based study was designed viz density functional theory (DFT) study to find the compounds’ stability and reactivity, molecular docking for estimating binding affinity, SeeSAR analysis and molecular dynamic simulations to confirm protein ligand complex stability and ADMET properties to find the pharmacokinetic profile of all compounds. The DFT results suggested that among all the derivatives, the 7g, 7j, and 7l were chemically reactive and stable derivatives. The optimized structures obtained from the DFTs were further selected for molecular docking, and the results suggested that 7g, 7j and 7l derivatives as the best inhibitors of VEGFR 2 with binding energy values −46.32, −48.89 and −45.01 kJ/mol. The Estimated inhibition constant (IC50) of hit compound 7j (0.009 µM) and simulation studies of its complexes confirms its high potency and best inhibitor of VEGFR2. All the derivatives were also docked with EGFR, where they showed weak binding energies and poor interactions, important compound 7g, 7j and 7i exhibited binding energy of −31.01, −33.23 and −34.19 kJ/mol respectively. Furthermore, the anticancer potential of the derivatives was confirmed by cell viability (MTT) assay using breast cancer and cervical cancer cell lines. At the end, the results of ADMET studies confirmed these derivatives as drug like candidates. Conclusively, the current study suggested substituted oxadiazoles as the potential anticancer compounds which exhibited more selectivity towards VEGFR2 in comparison to EGFR. Therefore, the identified lead molecules can be used for the synthesis of more potent derivatives of VEGFR2, along with extensive in vitro and in vivo experiments, that can be used to treat various cancers, especially renal cancers, and to prevent angiogenesis due to aberrant expression of VEGFR2.

Molecular Spectroscopy Evidence of 1,3,5-Tris(4-carboxyphenyl)benzene Binding to DNA: Anticancer Potential along with the Comparative Binding Profile of Intercalation via Modeling Studies

“…The effect was also observed against normal cell lines, i.e., African green monkey kidney (Vero) cells (ATTC: CCL-81™). The cell viability assay was accomplished by slightly modifying Mosmann’s 1983 and Nikš and Otto’s 1990 methods [ 27 , 28 ]. To each well, 10 × 10 4 cells were seeded and 10 μL of compound (and also doxorubicin and cisplatin) at the final concentration of 50 µM was treated with cells and then plates were kept in an incubator at 37 °C and 5% CO 2 .…”

Computational Exploration of Fluorocyclopentenyl‐purines and‐pyrimidines Derivatives as Potential Inhibitors of Epidermal Growth Factor Receptor (EGFR) for the Treatment of Breast Cancer

“…x=139.18, y=22.78, and z=48.91 angstroms, respectively and algorithm was set to retrieve 20 conformations for each derivative. The active site in the protein was determined using the “site finder” tool of the Molecular Operating Environment 2014.10 (MOE) software and the active pocket contained following amino acid residues: TYR867, ARG865, PRO853, VAL852, LYS851, GLY850, GLY849, GLU848, ALA847, TYR845, LYS836, ALA835, LEU834, GLY833, PHE832, ASP831, THR830, LEU820, ASP813, ARG812, THR766, ILE765, LEU764, CYS751, MET742, VAL741, GLU738, ASP737, ILE735, GLU734, LYS733, ALA731, LYS730, LEU723, LYS721, ILE720, ALA719, VAL702, PHE699 and ALA698 [26,27] …”

“…The active site in the protein was determined using the "site finder" tool of the Molecular Operating Environment 2014.10 (MOE) software and the active pocket contained following amino acid residues: TYR867, ARG865, PRO853, VAL852, LYS851, GLY850, GLY849, GLU848, ALA847, TYR845, LYS836, ALA835, LEU834, GLY833, PHE832, ASP831, THR830, LEU820, ASP813, ARG812, THR766, ILE765, LEU764, CYS751, MET742, VAL741, GLU738, ASP737, ILE735, GLU734, LYS733, ALA731, LYS730, LEU723, LYS721, ILE720, ALA719, VAL702, PHE699 and ALA698. [26,27] In order to validate the docking protocol, the co-crystal ligand was redocked into the active pocket of the protein and RMSD value of native pose and regenerated pose was compared. The RMSD value of less than 2 angstroms had validated the docking protocol.…”

Synthesis, docking study, and antitumor evaluation of benzamides and oxadiazole derivatives of 3‐phenoxybenzoic acid as VEGFR‐2 inhibitors

“…Figure 1j–l presents three potent oxadiazole pharmaceuticals that have received approval from the US Food and Drug Administration (FDA) and have been reported to possess anti‐cancerous properties (Siwach & Verma, 2020). Derivatives of 1,3,4 oxadiazole are also effective inhibitors of VEGFR‐2 and may be utilized for minimizing angiogenesis in malignancies that require selective VEGFR‐2 inhibitors (Bilal et al, 2022).…”