PMID: 11906282Mar 22, 2002Paper

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

Journal of Medicinal Chemistry
Shuanghong HuoIrwin D Kuntz

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 ...Continue Reading

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Citations

Jan 4, 2008·Journal of Molecular Modeling·Alexandre BeautraitBernard Maigret
Apr 14, 2010·Journal of Molecular Modeling·Claudio Carra, Francis A Cucinotta
Feb 3, 2011·Journal of Molecular Modeling·Mathew Varghese KoonammackalChellappanpillai Sudarsanakumar
Dec 14, 2011·Journal of Molecular Modeling·Claudio CarraFrancis A Cucinotta
Sep 11, 2008·Journal of Computer-aided Molecular Design·Jacob Kongsted, Ulf Ryde
Apr 20, 2010·Journal of Computer-aided Molecular Design·Natasja Brooijmans, Christine Humblet
May 4, 2012·Journal of Chemical Information and Modeling·Guoping HuYun Tang
Apr 14, 2012·Journal of Chemical Information and Modeling·Junmei Wang, Tingjun Hou
Jul 19, 2013·Journal of Chemical Information and Modeling·Qian ZhangTingjun Hou
Jul 10, 2013·Journal of Medicinal Chemistry·Isaac T SchieferGregory R J Thatcher
Nov 3, 2004·Nature Reviews. Drug Discovery·Douglas B KitchenJürgen Bajorath
Sep 3, 2004·Nucleic Acids Research·Michael TriebKlaus R Liedl
Feb 26, 2008·Folia Histochemica Et Cytobiologica·Alina MinarowskaŁukasz Minarowski
May 7, 2013·Expert Opinion on Drug Discovery·Martiniano BelloJosé Correa-Basurto
Nov 3, 2015·Journal of Chemical Information and Modeling·P HarisC Sudarsanakumar
Aug 23, 2011·Biotechnology Advances·Marco Daniele Parenti, Giulio Rastelli
Oct 30, 2015·Journal of Biomolecular Structure & Dynamics·Selvaraman NagamaniKarthikeyan Muthusamy
Jul 8, 2005·Proteins·Alain Laederach, Peter J Reilly
Jul 8, 2009·Journal of Molecular Recognition : JMR·César Millán-PachecoNina Pastor
Jun 6, 2007·British Journal of Pharmacology·S EkinsB Testa
Sep 22, 2012·Journal of Molecular Recognition : JMR·Sunil Kumar TripathiChandrabose Selvaraj
Sep 11, 2007·Biophysical Journal·Shin-ichi Fujiwara, Takashi Amisaki
Aug 4, 2004·Current Opinion in Chemical Biology·Juan C Alvarez

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