Structure-based identification of potent VEGFR-2 inhibitors from in vivo metabolites of a herbal ingredient

  • Raju Dash
  • Md. Junaid
  • Sarmistha Mitra
  • Md Arifuzzaman
  • S. M. Zahid HosenEmail author
Original Paper


Vascular endothelial growth factor receptor-2 (VEGFR-2) is one of the regulatory elements of angiogenesis that is expressed highly in various diseases and is also essential for solid tumor growth. The present study was aimed at identifying potent inhibitors of VEGFR-2 by considering herbal secondary metabolites; as natural molecules are less toxic than synthetic derivatives. A structure-based virtual screening protocol consisting of molecular docking, MM-GBSA and ADME/T analysis was initially used to screen a library of in vivo metabolites of the herbal ingredient. Using a fixed cutoff value, four potent virtual hits were identified from molecular docking, ADME/T and binding affinity calculations, which were considered further for molecular dynamics (MD) simulation to broadly describe the binding mechanisms to VEGFR-2. The results suggested that these molecules have high affinity for the catalytic region of VEGFR-2, and form strong hydrophobic and polar interactions with the amino acids involved in the binding site of ATP and linker regions of the catalytic site. Subsequently, the stability of the docked complexes and binding mechanisms were evaluated by MD simulations, and the energy of binding was calculated through MM-PBSA analysis. The results uncovered two virtual hits, designated ZINC14762520 and ZINC36470466, as VEGFR-2 inhibitors, and suggested that they bind to kinase domain in an ATP-competitive manner. These virtual hits will offer a suitable starting point for the further design of their various analogs, allowing a rational search for more effective inhibitors in the future.

Graphical abstract


VEGFR-2 Angiogenesis Molecular docking Molecular dynamics MM-PBSA 



Absorption distribution metabolism excretion and toxicity


Assisted model building with energy refinement


High throughout virtual screening


Kinase insert domain receptor


Molecular dynamics


Molecular mechanics


Molecular mechanics - generalized born and surface area


Optimized potential for liquid simulations


Poisson–Boltzmann surface area


Particle mesh Ewald


Radius of gyration


Root mean square deviation


Root mean square fluctuation


Structure activity relationship


Solvent accessible surface area


Surface generalized Born


Standard precision


The transferable intermolecular potential3 points


Vascular endothelial growth factor receptor 2


Extra precision


Yet another scientific artificial reality application



We thank Dr. Elmar Krieger, YASARA Biosciences GmbH, for providing an academic version of YASARA dynamics software. The authors acknowledge Prof. Gert Vriend (WHAT IF Foundation / CMBI, Netherlands) for his critical suggestions in Protein Dynamics Simulations. The authors are grateful to the Bangladesh Council of Scientific and Industrial Research for funding under the R&D project (SL. No. 42, 2016-17) to build a computational platform in Bangladesh.

Author contributions

R. D., S.M., S.M.Z.H. and M. A. planned experiments, analyzed data and prepared manuscript. R.D. S.M. and M. J performed experiments, and prepared the figures. All authors reviewed the manuscript.

Compliance with ethical standards

Competing financial interests

The authors declare no competing financial interests.

Supplementary material

894_2019_3979_MOESM1_ESM.doc (6.7 mb)
ESM 1 (DOC 6881 kb)
894_2019_3979_MOESM2_ESM.xls (62 kb)
ESM 2 (XLS 62 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Raju Dash
    • 1
    • 2
    • 3
  • Md. Junaid
    • 1
  • Sarmistha Mitra
    • 4
  • Md Arifuzzaman
    • 3
    • 5
  • S. M. Zahid Hosen
    • 1
    Email author
  1. 1.Molecular Modeling and Drug Design Laboratory, Pharmacology Research Division, Bangladesh Council of Scientific and Industrial Research (BCSIR)ChittagongBangladesh
  2. 2.Department of AnatomyDongguk University Graduate School of MedicineGyeongjuRepublic of Korea
  3. 3.Department of Biochemistry and BiotechnologyUniversity of Science and Technology ChittagongChittagongBangladesh
  4. 4.Plasma Bioscience Research Center, Plasma-bio displayKwangwoon UniversitySeoulRepublic of Korea
  5. 5.Department of Natural Sciences, LAGCCCity University of New York (CUNY)New YorkUSA

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