A Multistep Approach to Structure-Based Drug Design: Studying Ligand Binding at the Human Neutrophil Elastase (T. Steinbrecher, D. A. Case, and A. Labahn)

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A Multistep Approach to Structure-Based Drug
Design Studying Ligand Binding at the Human
Neutrophil Elastase(T. Steinbrecher, D. A. Case,
and A. Labahn)

• Richard S. L. Stein
• CS 379a
• March 14, 2006

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Modeling of HNE Inhibition

• Overabundance of human neutrophile elastase (HNE)
  degrades healthy tissue and results in various
  diseases
• Inhibitory action on HNE modeled by ligand
  docking calculations and molecular dynamics (MD)
  simulations of several known inhibitors of HNE
  structure dynamics analyzed by MM-PBSA method
• MD runs of 2 ns exhibited instability of many
  ligand-protein complexes
• Binding free energies from MD simulations
  disagreed with experiment
• The two most effective binding ligands, bornyl
  caffeate fukinolic acid, were each given 30
  docking placements divided into groups according
  to docking formation

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Bornyl Caffeate Fukinolic Acid(color
distinct placement within HNE)
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Docking Configuration Analysis

• MD simulation runs of 1 ns were performed on
  placement groups for bornyl caffeate and
  fukinolic acid, and closely related compounds
• Most stable ligand-protein complexes were further
  analyzed by thermodynamic integration (TI)
  calculations
• Binding free energies agreed with experiment
  better with bornyl caffeate derivatives than with
  fukinolic acid derivatives
• MD simulation analysis of bornyl caffeateHNE
  complex found a prospective binding mode
• Bornyl ferulate (a bornyl caffeate derivative)
  was found to bind more strongly to HNE with the
  transfer of a ring OH group
• Caffeic acid was found to bind significantly more
  weakly to HNE than bornyl caffeate, indicating
  importance of ligand hydrophobicity

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Advantages Drawbacks

• Advantages
• Combination of techniques (ligand docking, MD
  simulation and TI calculations) discovered a
  possible binding mode within HNE for bornyl
  caffeate
• Ability to propose binding modes for bornyl
  caffeate derivatives (ex. one conformation of
  bornyl ferulate)
• Drawbacks
• Failure to find binding mode for a good HNE
  inhibitor (fukinolic acid and its derivatives)
• MM-PBSA has statistical error (1 kcal/mol) equal
  to differences in binding free energies of
  similar placements for differing ligands (12
  kcal/mol)
• Length of simulations could more reliable
  ligand-protein complex stability data be obtained
  for runs longer than 1 ns?