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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Target the More Druggable Protein States in a Highly Dynamic Protein--Protein Interaction System

Zuojun Guo1, Atli Thorarensen1, Jianwei Che2

  • 1Worldwide Medicinal Chemistry, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.

Journal of Chemical Information and Modeling
|December 10, 2015
PubMed

Insights

Molecular dynamics simulations reveal Bcl-xL protein flexibility, showing its BH3 binding groove transitions between open and closed states. This flexibility is crucial for understanding and designing drugs targeting apoptosis regulation.

Area of Science:

  • Biochemistry and Molecular Biology
  • Computational Biology
  • Structural Biology

Background:

  • The Bcl-2 family proteins are critical regulators of programmed cell death (apoptosis).
  • Bcl-xL, a key member, controls mitochondrial outer membrane integrity during apoptosis initiation.
  • Understanding Bcl-xL's conformational dynamics is vital for structure-based drug design targeting apoptosis.

Purpose of the Study:

  • To investigate the conformational flexibility of the Bcl-xL protein.
  • To analyze the dynamic evolution of the ligand binding site (BH3 groove) in apo and holo states.
  • To assess the druggability of different Bcl-xL conformational states.

Main Methods:

  • Extensive molecular dynamics (MD) simulations using accelerated MD in Amber 14.
  • 200 ns simulation time for broad conformational sampling.
  • Pocket mining method with variational implicit-solvent model to assess ligand binding site druggability.

Main Results:

  • Bcl-xL exhibits significant conformational flexibility, particularly in the α3-helical domain and the α1-α2 loop.
  • The BH3 binding groove dynamically transitions between 'open' and 'closed' states, starting from an 'undruggable' apo crystal structure.
  • Approximately 10% of simulation frames showed moderate druggability, mimicking ligand-bound states.

Conclusions:

  • Bcl-xL's conformational plasticity is essential for its function and interaction with ligands.
  • Computer simulations can predict druggable conformational states of Bcl-xL, aiding drug design.
  • This approach enhances the success of structure-based drug design by identifying optimal binding conformations prior to synthesis.

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