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

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

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

Bornyl Caffeate & Fukinolic Acid (color = distinct placement within HNE)

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 caffeate—HNE 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

Advantages & Drawbacks 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 (1—2 kcal/mol) Length of simulations: could more reliable ligand-protein complex stability data be obtained for runs longer than 1 ns?