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.

Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models

“…Huo et al studied a set of cathepsin D (CatD) complexes by molecular docking, MD simulations and MM-PBSA calculations [54]. They were able to reproduce the experimental binding affinities for seven inhibitors of CatD with an average error of 1.0 kcal/mol and a correlation coefficient of 0.98, in contrast to the correlation coefficient of 0.2 of the docking scores.…”

“…As to for what systems MM-PBSA/GBSA tend to work well and for what systems not, in general, for systems that have substantial contributions to the free energy from buried charges, MM-PBSA/GBSA may not perform well; on the other hand, good results can be expected for the hydrophobic interaction dominated systems. Yet, this is not always the case and good results of both relative and absolute free energies could be observed for almost all kinds of systems, including proteins [14,44], nucleic acids [50][51], protein-ligand [13,54,63], and protein-protein [76][77][78][79]. It is emphasized that the above summary may be biased to some degree since we only selected some representative papers published recently in this field.…”

Human cathepsin D.

“…Polypeptide inhibitors of this proteinase occur in spare organs of many plants [108] and in tissues of some lower ani- mals [109,110]. Cathepsin D inhibitors have played a substantial role in the studies concerning the structure and mechanism of action of this protease and its tissue location [111][112][113][114][115].…”

On the consequences of placing amino groups at the TBP–DNA interface. Does TATA really matter?

“…As noted by Zhang and Schlick (and references therein), given the high charge density of both TBP and DNA, one of the main problems found with the calculation was the electrostatic contribution to the binding free energy. A possible solution to this electrostatic problem is to keep fixed those atoms outside the binding region (Wang et al, 2001;Huo et al, 2002). Despite the problems involved in the binding free energy calculation of highly charged molecules, these calculations reproduced the observed experimental ranking of TBP-DNA complexes (Zhang and Schlick, 2006).…”