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Insights into the conformational switching mechanism of the human vascular endothelial growth factor receptor type 2

Matteo Chioccioli1, Simone Marsili, Claudia Bonaccini

  • 1Laboratory of Molecular Modeling Cheminformatics and QSAR, Department of Pharmaceutical Sciences, University of Firenze, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze Italy.

Journal of Chemical Information and Modeling
|January 11, 2012
PubMed

Insights

Human vascular endothelial growth factor receptor type 2 (h-VEFGR2) kinase domain undergoes conformational changes crucial for drug targeting. Molecular dynamics simulations reveal intermediate states, aiding the design of selective anticancer drugs.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Human vascular endothelial growth factor receptor type 2 (h-VEFGR2) is a key regulator of angiogenesis and a significant target for anticancer drug development.
  • The receptor's kinase domain undergoes conformational changes, particularly involving the αC-helix and A-loop, which are critical for its activation and inactivation.
  • Understanding these conformational dynamics is essential for designing selective kinase inhibitors.

Purpose of the Study:

  • To investigate the conformational landscape of the kinase domain receptor (KDR) domain using molecular dynamics simulations.
  • To identify intermediate conformations between the active (DFG-in) and inactive (DFG-out) states.
  • To elucidate the atomistic mechanisms regulating A-loop opening and KDR domain conformational switching.

Main Methods:

  • Utilized molecular dynamics simulations to explore the conformational space of the KDR domain.
  • Employed targeted energy modifications to facilitate and observe the A-loop opening mechanism.
  • Analyzed simulation trajectories to identify rare intermediate conformations.

Main Results:

  • Successfully observed the KDR domain transitioning from the DFG-out conformation.
  • Identified novel intermediate conformations between the DFG-out and DFG-in states.
  • Provided atomistic insights into the regulation of the A-loop opening mechanism.

Conclusions:

  • Detailed knowledge of KDR domain conformational dynamics is vital for structure-based drug discovery.
  • The identified intermediate conformations represent potential new targets for enhancing inhibitor selectivity and efficacy.
  • This study provides a foundation for rational drug design targeting h-VEFGR2.

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