In Silico Discovery of Potential VEGFR-2 Inhibitors from Natural Derivatives for Anti-Angiogenesis Therapy

Abstract

Angiogenesis is the growth of new capillaries from existing blood vessels that supply oxygen and nutrients and provide gateways for immune surveillance. Abnormal vessel growth in term of excessive angiogenesis is a hallmark of cancer, inflammatory and eye diseases. VEGFR-2 (vascular endothelial growth factor receptor 2) dominating the process of angiogenesis has led to approval of therapeutic inhibitors and is becoming a promising target for anti-angiogenic drugs. Notwithstanding these successes, the clinical use of current VEGFR-2 blockers is more challenging than anticipated. Taking axitinib as a reference drug, in our study we found three potent VEGFR-2 inhibitors (ZINC08254217, ZINC08254138, and ZINC03838680) from natural derivatives. Each of the three inhibitors acquired a better grid score than axitinib (−62.11) when docked to VEGFR-2. Molecular dynamics simulations demonstrated that ZINC08254217– and ZINC08254138–VEGFR-2 complexes were more stable than axitinib. Similar to bind free energy for axitinib (−54.68 kcal/mol), such for ZINC03838680, ZINC08254217, and ZINC08254138 was −49.37, −43.32, and −32.73 kcal/mol respectively. These results suggested these three compounds could be candidate drugs against angiogenesis, with comparable VEGFR-2 binding affinity of axitinib. Hence findings in our study are able to provide valuable information on discovery of effective anti-angiogenesis therapy.

Discover natural compounds as potential phosphodiesterase-4B inhibitors via computational approaches

“…The energy minimization was performed to relax the complex system under 1000 kcal/mol/nm by using the steepest descent method.(J. Li et al, 2014) Afterwards, 100 ps NVT (constant number of particles, volume, and temperature) ensemble stabilized the system at 300 K and subsequently, 100 ps NPT (constant number of particles, pressure, and temperature) equilibration stabilized the system pressure by using coupling reference pressure of 1 bar. Finally, we ran the 10 ns MD simulation with a time step of 2 fs, storing corresponding coordinates every 2 ps.…”

Screening of multi-targeted natural compounds for receptor tyrosine kinases inhibitors and biological evaluation on cancer cell lines, in silico and in vitro

“…These receptors have recently caught the consciousness of the researchers as a stunning target to combat cancer owing to the proper documentation suggesting their over-expression on cancer cells. Number of reports confirm that, Green tea diminish the cell proliferation and promoted to cancer cell for growth inhibition in diverse cancer cells including colorectal, hepatocellular carcinoma cells, SW480 colon cancer cells, SV40 virally transformed WI38 human fibroblasts (WI38VA), prostate cancer, and Ishikawa cells [8][9][10][11][12][13].…”

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…115 Such design was based on earlier findings that urea-bearing pyrrolo [ Bao and co-workers identified three potential VEGFR-2 inhibitors (2-4) from the ZINC database through virtual screening and molecular docking analyses. 117 Molecular dynamics simulations demonstrated that these compounds could target VEGFR-2 with similar binding free energy for anitinib (-54.68 kcal/mol). Such results suggested that these compounds would bind to VEGFR-2-like anitinib with similar inhibition and antiangiogenic potency.…”

“…Bao and co‐workers identified three potential VEGFR‐2 inhibitors ( 2–4 ) from the ZINC database through virtual screening and molecular docking analyses . Molecular dynamics simulations demonstrated that these compounds could target VEGFR‐2 with similar binding free energy for anitinib (–54.68 kcal/mol).…”