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