title: Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions: insight into structure-based ligand design.
abstract: In this study, we compare the calculated and experimental binding free energies for a combinatorial library of inhibitors of cathepsin D (CatD), an aspartyl protease. Using a molecular dynamics (MD)-based, continuum solvent method (MM-PBSA), we are able to reproduce the experimental binding affinity for a set of seven inhibitors with an average error of ca. 1 kcal/mol and a correlation coefficient of 0.98. By comparing the dynamical conformations of the inhibitors complexed with CatD with the initial conformations generated by CombiBuild (University of California, San Francisco, CA, 1995), we have found that the docking conformation observed in an X-ray structure of one peptide inhibitor bound to CatD (Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6796-6800) is in good agreement with our MD simulation. However, the DOCK scoring function, based on intermolecular van der Waals and electrostatics, using a distance-dependent dielectric constant (J. Comput. Chem. 1992, 13, 505-524), poorly reproduces the trend of experimental binding affinity for these inhibitors. Finally, the use of PROFEC (J. Comput.-Aided Mol. Des. 1998, 12, 215-227) analysis allowed us to identify two possible substitutions to improve the binding of one of the better inhibitors to CatD. This study offers hope that current methods of estimating the free energy of binding are accurate enough to be used in a multistep virtual screening protocol.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0446, USA.
authors.forename: Shuanghong
authors.initials: S
authors.lastname: Huo
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.forename: Piotr
authors.initials: P
authors.lastname: Cieplak
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kollman
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Kuntz
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D002402:Cathepsin D / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D019151:Peptide Library; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012984:Software; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D008024:Ligands; D019151:Peptide Library; D002402:Cathepsin D