Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions: Insight into structure-based ligand design

Shuanghong Huo, Junmei Wang, Piotr Cieplak, Peter A. Kollman, Irwin D. Kuntz

Research output: Contribution to journalArticle

162 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1412-1419
Number of pages8
JournalJournal of Medicinal Chemistry
Volume45
Issue number7
DOIs
StatePublished - Mar 28 2002

Fingerprint

Cathepsin D
Molecular Dynamics Simulation
Free energy
Molecular dynamics
Ligands
Conformations
Aspartic Acid Proteases
San Francisco
Static Electricity
Electrostatics
Screening
Permittivity
Substitution reactions
X-Rays
X rays
Peptides
Computer simulation

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions : Insight into structure-based ligand design. / Huo, Shuanghong; Wang, Junmei; Cieplak, Piotr; Kollman, Peter A.; Kuntz, Irwin D.

In: Journal of Medicinal Chemistry, Vol. 45, No. 7, 28.03.2002, p. 1412-1419.

Research output: Contribution to journalArticle

Huo, Shuanghong ; Wang, Junmei ; Cieplak, Piotr ; Kollman, Peter A. ; Kuntz, Irwin D. / Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions : Insight into structure-based ligand design. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 7. pp. 1412-1419.
@article{38b9bf069c36495c9ff3df8e6c3ab9da,
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.",
author = "Shuanghong Huo and Junmei Wang and Piotr Cieplak and Kollman, {Peter A.} and Kuntz, {Irwin D.}",
year = "2002",
month = "3",
day = "28",
doi = "10.1021/jm010338j",
language = "English (US)",
volume = "45",
pages = "1412--1419",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions

T2 - Insight into structure-based ligand design

AU - Huo, Shuanghong

AU - Wang, Junmei

AU - Cieplak, Piotr

AU - Kollman, Peter A.

AU - Kuntz, Irwin D.

PY - 2002/3/28

Y1 - 2002/3/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037187412&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037187412&partnerID=8YFLogxK

U2 - 10.1021/jm010338j

DO - 10.1021/jm010338j

M3 - Article

C2 - 11906282

AN - SCOPUS:0037187412

VL - 45

SP - 1412

EP - 1419

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -