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Exploration of the valproic acid binding site on histone deacetylase 8 using docking and molecular dynamic

Jorge Antonio Bermúdez-Lugo1, Oscar Perez-Gonzalez, Martha Cecilia Rosales-Hernández

  • 1Sección de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Mexico City, Mexico.

Journal of Molecular Modeling
|October 5, 2011
PubMed

Insights

Valproic acid (VPA) shows low affinity at the catalytic site of HDAC but binds strongly to the hydrophobic active site channel (HASC). This binding, driven by hydrophobic and hydrogen bonding interactions, suggests HASC

Area of Science:

  • Biochemistry
  • Pharmacology
  • Computational Chemistry

Background:

  • Epigenetic therapy is crucial for cancer drug development.
  • Valproic acid (VPA) is an established HDAC inhibitor in clinical cancer treatment.
  • The precise mechanism of VPA's HDAC inhibition remains unclear.

Purpose of the Study:

  • To elucidate the binding mechanism of VPA to HDAC.
  • To investigate VPA interactions at both the catalytic site (CS) and the hydrophobic active site channel (HASC).
  • To determine the binding affinity and key interactions driving VPA's effect on HDAC.

Main Methods:

  • Molecular docking simulations were employed to predict VPA binding modes.
  • Molecular dynamic (MD) simulations were used to analyze VPA-HDAC interactions over time.
  • Both native and rebuilt 3-D structures of HDAC were utilized.

Main Results:

  • VPA exhibits low affinity for the HDAC catalytic site (CS) through coordination with Zn and local residues.
  • VPA demonstrates significantly higher affinity for the hydrophobic active site channel (HASC).
  • VPA's high affinity for HASC is attributed to van der Waals and hydrogen bonding interactions with channel residues.

Conclusions:

  • The hydrophobic active site channel (HASC) is a potential key site for VPA's HDAC inhibition mechanism.
  • VPA's binding to HASC, influenced by channel dynamics, offers a new perspective on its therapeutic action.
  • Further research into HASC-VPA interactions could lead to more effective epigenetic cancer therapies.

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