Molecular dynamics guided insight, binding free energy calculations and pharmacophore-based virtual screening for the identification of potential VEGFR2 inhibitors

Ekta Rathi, Avinash Kumar, Suvarna G. Kini

Research output: Contribution to journalArticle

Abstract

Vascular endothelial growth factor-A (VEGF-A) is a crucial member of the Vascular endothelial growth factor (VEGF) family which mediates the metastasis of tumor by ‘angiogenic switch’. Therefore, targeting a VEGF-A mediated VEGFR2 signaling pathway is the most promising approach to repress the angiogenesis of tumor cells. VEGFR2 inhibitors are two types: Type I and Type II. Type II inhibitors have more chemical space to exploit and have better selectivity because of allosteric binding pocket over type I inhibitors. Hence, The present study encompasses identification of potential type II VEGFR2 inhibitors employing pharmacophore based virtual screnning. In this study, ten five featured pharmacophore model were generated from a dataset of 39 biaryl urea analogs.Out of all, ADDRR_1 pharmacophore model were used to screen the library of 5.2 million compounds retrieved from NCI, Maybridge, Asinex and Zinc databases. 7000 hits were filtered out from the pharmacophore-based virtual screening based on the phase fitness score. Among all best ten hits were identified employing extra precision mode of GLIDE module. ZINC00759038 and 211246 were chosen as top hits based on docking score, free binding energy, and ADME profile. They were subjected to molecular-dynamic studies to assess the hits-VEGFR2 binding stability. It suggests that ZINC00759038-VEGFR2 and 211246-VEGFR2 complexes are quite stable for the 20 ns simulation period. The strength of hit-protein complexes were further assessed by thermodynamic analysis of MD simulation studies by MMGBSA. Interestingly, these hits retains 90% similarity with standard VEGFR2 inhibitor (Sorafenib). Hence, these identified hits may led to new lead compounda as VEGFR2 inhibitors.

Original languageEnglish
JournalJournal of Receptors and Signal Transduction
DOIs
Publication statusAccepted/In press - 01-01-2019

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Molecular Dynamics Simulation
Vascular Endothelial Growth Factor A
Free energy
Molecular dynamics
Screening
Tumors
Binding energy
Thermodynamics
Urea
Zinc
Neoplasms
Cells
Switches
Databases
Neoplasm Metastasis
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Molecular dynamics guided insight, binding free energy calculations and pharmacophore-based virtual screening for the identification of potential VEGFR2 inhibitors",
abstract = "Vascular endothelial growth factor-A (VEGF-A) is a crucial member of the Vascular endothelial growth factor (VEGF) family which mediates the metastasis of tumor by ‘angiogenic switch’. Therefore, targeting a VEGF-A mediated VEGFR2 signaling pathway is the most promising approach to repress the angiogenesis of tumor cells. VEGFR2 inhibitors are two types: Type I and Type II. Type II inhibitors have more chemical space to exploit and have better selectivity because of allosteric binding pocket over type I inhibitors. Hence, The present study encompasses identification of potential type II VEGFR2 inhibitors employing pharmacophore based virtual screnning. In this study, ten five featured pharmacophore model were generated from a dataset of 39 biaryl urea analogs.Out of all, ADDRR_1 pharmacophore model were used to screen the library of 5.2 million compounds retrieved from NCI, Maybridge, Asinex and Zinc databases. 7000 hits were filtered out from the pharmacophore-based virtual screening based on the phase fitness score. Among all best ten hits were identified employing extra precision mode of GLIDE module. ZINC00759038 and 211246 were chosen as top hits based on docking score, free binding energy, and ADME profile. They were subjected to molecular-dynamic studies to assess the hits-VEGFR2 binding stability. It suggests that ZINC00759038-VEGFR2 and 211246-VEGFR2 complexes are quite stable for the 20 ns simulation period. The strength of hit-protein complexes were further assessed by thermodynamic analysis of MD simulation studies by MMGBSA. Interestingly, these hits retains 90{\%} similarity with standard VEGFR2 inhibitor (Sorafenib). Hence, these identified hits may led to new lead compounda as VEGFR2 inhibitors.",
author = "Ekta Rathi and Avinash Kumar and Kini, {Suvarna G.}",
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AB - Vascular endothelial growth factor-A (VEGF-A) is a crucial member of the Vascular endothelial growth factor (VEGF) family which mediates the metastasis of tumor by ‘angiogenic switch’. Therefore, targeting a VEGF-A mediated VEGFR2 signaling pathway is the most promising approach to repress the angiogenesis of tumor cells. VEGFR2 inhibitors are two types: Type I and Type II. Type II inhibitors have more chemical space to exploit and have better selectivity because of allosteric binding pocket over type I inhibitors. Hence, The present study encompasses identification of potential type II VEGFR2 inhibitors employing pharmacophore based virtual screnning. In this study, ten five featured pharmacophore model were generated from a dataset of 39 biaryl urea analogs.Out of all, ADDRR_1 pharmacophore model were used to screen the library of 5.2 million compounds retrieved from NCI, Maybridge, Asinex and Zinc databases. 7000 hits were filtered out from the pharmacophore-based virtual screening based on the phase fitness score. Among all best ten hits were identified employing extra precision mode of GLIDE module. ZINC00759038 and 211246 were chosen as top hits based on docking score, free binding energy, and ADME profile. They were subjected to molecular-dynamic studies to assess the hits-VEGFR2 binding stability. It suggests that ZINC00759038-VEGFR2 and 211246-VEGFR2 complexes are quite stable for the 20 ns simulation period. The strength of hit-protein complexes were further assessed by thermodynamic analysis of MD simulation studies by MMGBSA. Interestingly, these hits retains 90% similarity with standard VEGFR2 inhibitor (Sorafenib). Hence, these identified hits may led to new lead compounda as VEGFR2 inhibitors.

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