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Drug Design
From Structure and Mode-of-Action to Rational Design Concepts
Gerhard Klebe
Drug Design
From Structure and Mode-of-Action to Rational Design Concepts
Gerhard Klebe
Institute of Pharmaceutical Chemistry
Philipps-University Marburg
Marburg, Germany
ISBN 978-3-662-68997-4 ISBN 978-3-662-68998-1 (eBook)
https://doi.org/10.1007/978-3-662-68998-1
Translation from the German language edition: “Wirkstoffdesign: Entwurf und Wirkung von Arzneistoffen” by
Gerhard Klebe, © Der/die Herausgeber bzw. der/die Autor(en), exklusiv lizenziert an Springer-Verlag GmbH,
DE, ein Teil von Springer Nature 2024. Published by Springer Berlin Heidelberg. All Rights Reserved.
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part
of Springer Nature 2024
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the
material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and
retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or
hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does
not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective
laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book are
believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors
give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions
that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps
and institutional affiliations.
Cover illustration: Crystal structures of human protein kinase A with ligands derived from fragment discovery
and optimization (PDB codes: 3OOG, 3OVV, 3OXT, 3P0M) summarized in the Ph.D. thesis of Dr. Helene Köster,
Univ. Marburg (2012), (https://d-nb.info/102718376X/34).
This Springer imprint is published by the registered company Springer-Verlag GmbH, DE, part of Springer Nature.
The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany
If disposing of this product, please recycle the paper.
Scientists have searched for aperpetuum mobile.
They have found it: It is science itself.
Victor Hugo
V
VI
Preface and Acknowledgement
The present Drug Design textbook is based on the German version rst written by
Hans-Joachim Böhm, Hugo Kubinyi, and me in 1996. After several years of success on
the market, the German version was completely rewritten and signicantly expanded.
Ithank my two former coauthors for allowing me to reuse some of their passages from
the original version in this edition.
Meanwhile, athird German edition is available. Several attempts have been made
to translate this book into English to make it available to awider audience. The reason
for this was that the author was repeatedly asked why such asuccessful book was not
available in English. An analysis of the textbook market revealed that no similar compendium covering the same area of interest was available. Springer agreed to atranslation project, and in 2013, Dr. Leila Telan, agifted bilingual medicinal chemist and
physician, produced arst translation of the German second edition. It was available
in the Springer Reference series, but not yet with the accessibility the author desired as
an affordable textbook for students. Even atranslation into Chinese as atextbook was
achieved in 2018. Thus, to realize the idea of an English textbook version, the author
took the opportunity to translate the third German edition with the help of the earlier
handbook copy. This book is intended for students of chemistry, pharmacy, biochemistry, biology, chemical biology, and medicine who are interested in the design of new
drugs and the structural basis of drug action. It is also tailored for practitioners in the
pharmaceutical industry who want amore comprehensive overview of various aspects
of the drug discovery process.
In the 15years since the second German edition was published, many areas of drug
design have matured and are now an integral part of drug discovery worldwide. The
eld has continued to benet enormously from the steady increase in computing power.
Many techniques, such as virtual screening or mining large databases, have become
signicantly faster and more comprehensive. However, for aquantum leap in performance and reliability, abetter understanding of the biophysical principles of molecular
recognition still needs to be incorporated into the methods. Machine learning and articial intelligence have brought many algorithms to higher levels of performance. One
example is protein structure prediction from asequence. It has now reached alevel of
reliability that qualies it for predicting new spatial structures. Real innovations have
been observed in the eld of experimental structure determination. Cryo-electron microscopy allows us to gain insight into large biomolecules such as ion channels or G-protein-coupled receptors. Although these biomolecules have been drug targets for decades,
there has been alack of structural information to truly understand their mechanisms
of action. Today, it is even more obvious that models cannot replace this. The search
for lead structures is increasingly based on fragment-based lead discovery methods. If
you compare drug design today with the early days 40years ago, we are tackling much
more difcult targets, such as modulating protein communication with small molecules.
So the real advances are in addressing increasingly complex mechanisms of action. We
are also thinking more about the temporal and energetic sequence of binding processes
and how the dynamics of the molecules involved determine the mode of action and
the therapeutic prole of putative drug molecules. All the more reason for atextbook
author to ask the question: How can one provide an overview of this ever-growing eld?
An exemplary selection of the examples to be considered is essential. They must be
representative of many other works that remain unnamed. Of course, it is particularly
appealing to take up and present the new aspects. However, the origins of drug design
must not be lost. This is the only way to understand how the eld has evolved. Older
methods, which still play an important role in daily work, should not be completely
ignored. This book is, therefore, acompromise between the old and the new. It tries to
pass on my own enthusiasm and fascination for this eld of research to young scientists.
What better way to do this than with atextbook? It can present content from adifferent
perspective and show cross-references between individual aspects in away that is hardly
Preface and Acknowledgement
VII
possible in an original research paper or areview article, especially since such reports
are often only really comprehensible to experts.
Numerous colleagues have contributed to the success of this book by critically reviewing various passages and chapters and by providing many comments. In particular,
Iwould like to thank my colleagues in Marburg, Prof. Dr. Andreas Heine and Prof.
Dr. Klaus Reuter, for their fruitful collaboration and many discussions over more than
20years, and some of the concepts we developed together have found their way into
this book. In Marburg, Iwould also like to thank Dr. Daniel Hilger, Prof. Dr. Jens
Kockskämper, Dr. Dzung Nguyen, and Dr. Doro Vornicescu for many suggestions
and for proofreading individual chapters. Outside Marburg, Iwould like to thank Prof.
Dr. Paul Czodrowski (Mainz, Germany), Dr. Stefan Duhr (Munich, Germany), Prof.
Dr. Richard Engh (Tromsø, Norway), Prof. Dr. Oliver Ernst (Toronto, Canada), Dr.
Michael Hennig (Villigen, Switzerland), Dr. Wolfgang Jahnke (Basel, Switzerland), Dr.
Gerhard Müller (Munich, Germany), Prof. Dr. John Ladbury (Leeds, United Kingdom), Prof. Dr. Milton Stubbs (Halle, Germany), Prof. Dr. Matthias Rarey (Hamburg,
Germany), Dr. Ulrich Rant (Munich, Germany), Prof. Dr. Peter Tonge (Stony Brook,
New York, USA), and Prof. Dr. Daniel Wilson (Hamburg, Germany) for their comments and careful editing.
Dr. Christoph Sager (Basel, Switzerland) kindly programmed the platform and
made the videos for the illustrations available on YouTube. Iwould also like to thank
Ms. Susanne Dathe (Springer-Verlag Heidelberg) for her exemplary support during the
production of this book.
Gerhard Klebe
Frankfurt, Germany
Chemical Structures of Amino Acids, Molecular Graphics and Introduction
IX
abc
X Chemical Structures of Amino Acids, Molecular Graphics and Introduction
de f
7 https://sn.pub/dfOc6R
This gure explains how the protein structures and bound ligands are represented in
many of the gures in this book. In the upper left, the protein is schematically represented by the course of its main chain. Segments of the polymer chain with afolded
sheet structure (as arrows) are highlighted in light-blue, helical segments (as cylinders)
in red, and loop regions in green. At the top center, amino acid residues in the active site
are shown in astick representation. Unless otherwise noted, protein carbon atoms are
shown in orange, ligand carbon atoms in gray, oxygen atoms in red, nitrogen atoms in
blue, sulfur atoms in yellow, phosphorus atoms in orange, uorine atoms in turquoise,
chlorine atoms in green, bromine atoms in brown, iodine atoms in purple, and metal
ions in grayish blue. Hydrogen atoms are white, but are usually omitted for clarity. At
the top right, amino acids are identied by athree-letter code and their position in the
sequence (e.g., His94). Hydrogen bonds between the ligand (here para-uorophenylsul-
fonamide) and the amino acids of the protein are indicated by thin light-green lines. In
the lower left corner, around the binding pocket (asection of the structure is shown), the
solvent-accessible surface has been calculated (see Sect.15.6) and is indicated as apale
gray-white area. In the center below is an analogous representation of the surface, now
transparent, along with the amino acid residues of the binding pocket. At the bottom
right is an overall view of the protein (in this case carbonic anhydraseII, see Sect.25.7
for details), with the indicated binding pocket of the catalytic center blocked by an
inhibitor. It coordinates to the zinc ion and forms three hydrogen bonds to the protein.
The polymer chain is shown as acontinuous ribbon model. The color coding, with light
blue, red and green sections, corresponds to that in the gure above left.
The illustrations were created using Discovery Studio Visualizer V20.1.0.19295 from
Dassault Systemes Biovia Corp., Copyright 2019. Together with this book, the reader
can access these gures as videos in the form of moving images using the provided QR
codes or Springer’s tiny URLs linking to 7 https://drugdesign.ch/en. In the electronic
pdf version, the URLs are linked directly and can be accessed by clicking on them. The
videos have been uploaded to YouTube and can be viewed on standard mobile phones,
tablets, or desktop computers using the browsers installed on these devices. The settings
in these browsers will need to be adjusted to display YouTube videos. The book contains
many internal links to Chapters, Sections, Figures or Tables, highlighted in blue. In the
pdf version they can be activated by clicking on them. To return, please use the [ALT
+ <] key combination.
Chemical Structures of Amino Acids, Molecular Graphics and Introduction
XI
When considering the diversity of all possible chemical compounds, acomparison with
the innite vastness of the universe is often made. If one does not limit oneself to the
compounds that have actually been synthesized to date, but also generates molecules
on the computer that can in principle be synthesized but have not yet been produced,
gigantically large numbers of molecules can be generated. If one also takes into account
the many stereoisomers that can be generated for complex organic molecules, the number becomes even larger. The art of rational drug design is now to sh out of the vast
universe of all conceivable chemical compounds the right one that inhibits the target
protein under consideration in ahighly potent and selective manner. This gure shows
NAPAP, one of the rst highly potent thrombin inhibitors. For many years, it has served
as alead structure for the development of inhibitors of trypsin-like serine proteases. It
binds deeply into the so-called S1 pocket of the enzyme thrombin, which plays acentral role in blood clotting. The inhibitor NAPAP is shown here atom color-coded, with
atranslucent white surface. Its binding site in the protein is represented by aplastic
surface that changes its color from blue (outside), to green, and to red (deeply buried),
depending on the depth of the depression of the binding site. The structures of protein
kinaseA with four ligands are shown on the cover of this book. Starting with aweakly
binding millimolar fragment (red surface), this initial hit was optimized in several iterative design cycles to ananomolar ligand (blue surface). The spatial structures of proteins
and ligands are sketched in the background, symbolizing the universe of all possible
molecular structures. This book explains how the structures of ligands and proteins can
be used to develop potent drug candidates using computer modeling, chemical synthesis,
screening, and binding assays. (7 https://sn.pub/4NppHn)