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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


IMPACT FACTOR 2018: 3.014
5-year IMPACT FACTOR: 3.162

CiteScore 2018: 3.09

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Source Normalized Impact per Paper (SNIP) 2018: 0.820

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1437-4315
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Volume 395, Issue 7-8

Issues

Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues

Anastasia Tziridis
  • Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 3, D-06120 Halle/Saale, Germany
  • Other articles by this author:
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/ Daniel Rauh
  • Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 3, D-06120 Halle/Saale, Germany
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/ Piotr Neumann
  • Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 3, D-06120 Halle/Saale, Germany
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/ Petr Kolenko
  • Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 3, D-06120 Halle/Saale, Germany
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/ Anja Menzel
  • Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 3, D-06120 Halle/Saale, Germany
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/ Ulrike Bräuer
  • Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 3, D-06120 Halle/Saale, Germany
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/ Christian Ursel
  • Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 3, D-06120 Halle/Saale, Germany
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/ Peter Steinmetzer
  • Institut für Vaskuläre Medizin und Biologie, Friedrich-Schiller-Universität Jena, Nordhäuser Straße 78, D-99089 Erfurt, Germany
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/ Jörg Stürzebecher
  • Institut für Vaskuläre Medizin und Biologie, Friedrich-Schiller-Universität Jena, Nordhäuser Straße 78, D-99089 Erfurt, Germany
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/ Andrea Schweinitz / Torsten Steinmetzer / Milton T. Stubbs
  • Corresponding author
  • Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 3, D-06120 Halle/Saale, Germany
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Published Online: 2014-07-08 | DOI: https://doi.org/10.1515/hsz-2014-0158

Abstract

A high-resolution crystallographic structure determination of a protein–ligand complex is generally accepted as the ‘gold standard’ for structure-based drug design, yet the relationship between structure and affinity is neither obvious nor straightforward. Here we analyze the interactions of a series of serine proteinase inhibitors with trypsin variants onto which the ligand-binding site of factor Xa has been grafted. Despite conservative mutations of only two residues not immediately in contact with ligands (second shell residues), significant differences in the affinity profiles of the variants are observed. Structural analyses demonstrate that these are due to multiple effects, including differences in the structure of the binding site, differences in target flexibility and differences in inhibitor binding modes. The data presented here highlight the myriad competing microscopic processes that contribute to protein–ligand interactions and emphasize the difficulties in predicting affinity from structure.

This article offers supplementary material which is provided at the end of the article.

Keywords: crystal structure; factor Xa; ligand affinity; protein flexibility; selectivity; structure-based drug design

Dedicated to the memory of our friend and colleague Professor Dr. Jörg Stürzebecher, whose untimely death was a tragic loss to us and to the scientific community.

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About the article

Corresponding author: Milton T. Stubbs, Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 3, D-06120 Halle/Saale, Germany, e-mail:

aPresent address: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, D-65926 Frankfurt/Main, Germany.

bPresent address: Fakultät für Chemie und Chemische Biologie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.

cPresent address: Institut für Mikrobiologie und Genetik, Georg-August-Universität, Justus-von-Liebig-Weg 11, D-37077 Göttingen, Germany.

dPresent address: Institute of Macromolecular Chemistry, Heyrovského nám. 2, CZ-162 06 Praha 6, Czech Republic.

ePresent address: Institut für Rechtsmedizin, Otto-von-Guerike-Universität, Leipziger Str. 44, D-39120 Magdeburg, Germany.

fPresent address: School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

gPresent address: Institut für Physiologie II, Universitätsklinikum Jena, Kollegiengasse 9, D-07743 Jena, Germany.

hPresent address: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.


Received: 2014-03-03

Accepted: 2014-04-24

Published Online: 2014-07-08

Published in Print: 2014-07-01


Citation Information: Biological Chemistry, Volume 395, Issue 7-8, Pages 891–903, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2014-0158.

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