3D QSAR

in Drug Design
Recent Advances
QSAR = Three-Dimensional Quantitative Structure Activity Relationships
VOLUME 3

The titles published in this series are listed at the end of this volume.
3D QSAR
in Drug Design
Volume 3
Recent Advances

Edited by

Hugo Kubinyi
ZHF/G, A30, BASF AG, D-67056 Ludwigshafen, Germany
Gerd Folkers
ETH-Zürich, Department Pharmazie, Winterthurer Strasse 190, CH-8057 Zürich,
Switzerland
Yvonne C. Martin
Abbott Laboratories, Pharmaceutical Products Division, 100 Abbott Park Rd.,
Abbott Park, IL 60064-3500, USA

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 Contents

Preface vii

Part I. 3D QSAR Methodology. CoMFA and Related Approaches

3D QSAR: Current State, Scope, and Limitations 3

Yvonne Connolly Martin

Recent Progress in CoMFA Methodology and Related Techniques 25

UlfNorinder

Improving the Predictive Quality of CoMFA Models 41

Romano T. Kroemer, Peter Hecht, Stefan Guessregen and Klaus R. Liedl

Cross-Validated Guided Region Selection for CoMFA Studies 57

Alexander Tropsha and Sung Jin Cho

GOLPE-Guided Region Selection 71

Gabriele Cruciani, Sergio dementi and Manuel Pastor

Comparative Molecular Similarity Indices Analysis: CoMSIA 87

Gerhard Klebe

Alternative Partial Least Squares (PLS) Algorithms 105

Fredrik Lindgren and Stefan Rännar

Part II. Receptor Models and Other 3D QSAR Approaches

Receptor Surface Models 117

Mathew Hahn and David Rogers

Pseudoreceptor Modelling in Drug Design: Applications of Yak and PrGen 135

Marion Gurrath, Gerhard Müller and Hans-Dieter Höltje

Genetically Evolved Receptor Models (GERM) as a 3D QSAR Tool 159

D. Eric Walters

3D QSAR of Flexible Molecules Using Tensor Representation 167

William J. Dunn and Antony J. Hopfinger

v
Contents

Comparative Molecular Moment Analysis (CoMMA) 183

B. David Silverman, Daniel E. Plan, Mike Pitman and Isidore Rigoutsos

Part III. 3D QSAR Applications

The CoMFA Steroids as a Benchmark Dataset for Development of 199
3D QSAR Methods
Eugene A. Coats

Molecular Similarity Characterization using CoMFA 215

Thierry Langer

Building a Bridge between G-Protein-Coupled Receptor Modelling, Protein 233

Crystallography and 3D QSAR Studies for Ligand Design
Ki Hwan Kim

A Critical Review of Recent CoMFA Applications 257

Ki Hwan Kim, Giovanni Greco and Ettore Novellino

List of CoMFA References, 1993-1996 317

List of COMFA References, 1997 334

Ki Hwan Kim

Author Index 339

Subject Index 341

vi
 Preface

Significant progress has been made in the study of three-dimensional quantitative

structure-activity relationships (3D QSAR) since the first publication by Richard
Cramer in 1988 and the first volume in the series, 3D QSAR in Drug Design. Theory,
Methods and Applications, published in 1993. The aim of that early book was to
contribute to the understanding and the further application of CoMFA and related
approaches and to facilitate the appropriate use of these methods.
Since then, hundreds of papers have appeared using the quickly developing techniques
of both 3D QSAR and computational sciences to study a broad variety of biological
problems. Again the editor(s) felt that the time had come to solicit reviews on published
and new viewpoints to document the state of the art of 3D QSAR in its broadest
definition and to provide visions of where new techniques will emerge or new applica-
tions may be found. The intention is not only to highlight new ideas but also to show the
shortcomings, inaccuracies, and abuses of the methods. We hope this book will enable
others to separate trivial from visionary approaches and me-too methodology from inno-
vative techniques. These concerns guided our choice of contributors. To our delight, our
call for papers elicited a great many manuscripts. These articles are collected in two
bound volumes, which are each published simultaneously in two related series: they form
Volumes 2 and 3 of the 3D QSAR in Drug Design series which correspond to volumes
9–11 and 12–14, respectively, in Perspectives in Drug Discovery and Design. Indeed, the
field is growing so rapidly that we solicited additional chapters even as the early chapters
were being finished. Ultimately it will be the scientific community who will decide if the
collective biases of the editors have furthered development in the field.
The challenge of the quantitative prediction of the biological potency of a new mole-
cule has not yet been met. However, in the four years since the publication of the first
volume, there have been major advances in our understanding of ligand-receptor inter-
actions, molecular s i m i l a r i t y , pharmacophores, and macromolecular structures.
Although currently we are well prepared computationally to describe ligand-receptor
interactions, the thorny problem lies in the complex physical chemistry of inter-
molecular interactions. Structural biologists, whether experimental or theoretical in
approach, continue to struggle with the field’s limited quantitative understanding of the
enthalpic and entropic contributions to the overall free energy of binding of a ligand to a
protein. With very few exceptions, we do not have experimental data on the thermo-
dynamics of intermolecular interactions. The recent explosion of 3D protein structures
helps us to refine our understanding of the geometry of ligand-protein complexes.
However, as traditionally practiced, both crystallographic and NMR methods yield
static pictures and relatively coarse results considering that an attraction between two
non-bonded atoms may change to repulsion within a tenth of an This is well
below the typical accuracy of either method. Additionally, neither provides information
about the energetics of the transfer of the ligand from solvent to the binding site.
Preface

With these challenges in mind, one aim of these volumes is to provide an overview of
the current state of the quantitative description of ligand-receptor interactions. To aid
this understanding, quantum chemical methods, molecular dynamics simulations and
the important aspects of molecular similarity of protein ligands are treated in detail in
Volume 2. In the first part ‘Ligand–Protein Interactions,’ seven chapters examine the
problem from very different points of view. Rule- and group-contribution-based ap-
proaches as well as force-field methods are included. The second part ‘Quantum
Chemical Models and Molecular Dynamics Simulations’ highlights the recent ex-
tensions of ab initio and semi-empirical quantum chemical methods to ligand-protein
complexes. An additional chapter illustrates the advantages of molecular dynamics
simulations for the understanding of such complexes. The third part ‘Pharmacophore
Modelling and Molecular Similarity’ discusses bioisosterism, pharmacophores and
molecular similarity, as related to both medicinal and computational chemistry. These
chapters present new techniques, software tools and parameters for the quantitative
description of molecular similarity.
Volume 3 describes recent advances in Comparative Molecular Field Analysis and
related methods. In the first part ‘3D QSAR Methodology. CoMFA and Related
Approaches’, two overviews on the current state, scope and limitations, and recent
progress in CoMFA and related techniques are given. The next four chapters describe
improvements of the classical CoMFA approach as well as the CoMSIA method, an
alternative to CoMFA. The last chapter of this part presents recent progress in Partial
Least Squares (PLS) analysis. The part ‘Receptor Models and Other 3D QSAR
Approaches’ describes 3D QSAR methods that are not directly related to CoMFA, i.e.,
Receptor Surface Models, Pseudo-receptor Modelling and Genetically Evolved
Receptor Models. The last two chapters describe alignment-free 3D QSAR methods.
The part ‘3D QSAR Applications’ completes Volume 3. It gives a comprehensive
overview of recent applications but also of some problems in CoMFA studies. The first
chapter should give a warning to all computational chemists. Its conclusion is that all
investigations on the classic corticosteroid-binding globulin dataset suffer from serious
errors in the chemical structures of several steroids, in the affinity data and/or in their
results. Different authors made different mistakes and sometimes the structures used in
the investigations are different from the published structures. Accordingly it is not poss-
ible to make any exact comparison of the reported results! The next three chapters
should be of great value to both 3D QSAR practitioners and to medicinal chemists, as
they provide overviews on CoMFA applications in different fields, together with a
detailed evaluation of many important CoMFA publications. Two chapters by Ki Kirn
and his comprehensive list of 1993–1997 CoMFA papers are a highly valuable source
of information.
These volumes are written not only for QSAR and modelling scientists. Because of
their broad coverage of ligand binding, molecular similarity, and pharmacophore and
receptor modelling, they will help synthetic chemists to design and optimize new leads,
especially to a protein whose 3D structure is known. Medicinal chemists as well as agri-
cultural chemists, toxicologists and environmental scientists will benefit from the de-
scription of so many different approaches that are suited to correlating structure-activity
 Preface

relationships in cases where the biological targets, or at least their 3D structures, are still
unknown.
This project would not have been realized without the ongoing enthusiasm of Mrs.
Elizabeth Schram, founder and former owner of ESCOM Science Publishers, who initi-
ated and strongly supported the idea of publishing further volumes on 3D QSAR in
Drug Design. Special thanks belong also to Professor Robert Pearlman, University of
Texas, Austin, Texas, who was involved in the first planning and gave additional
support and input. Although during the preparation of the chapters Kluwer Academic
Publishers acquired ESCOM, the project continued without any break or delay in the
work. Thus, the Editors would also like to thank the new publisher, especially Ms.
Maaike Oosting and Dr. John Martin, for their interest and open-mindedness, which
helped to finish this project in time.
Lastly, the Editors are grateful to all the authors. They made it possible for these
volumes to be published only 16 months after the very first author was contacted. It is
the authors’ diligence that has made these volumes as complete and timely as was
Volume 1 on its publication in 1993.
Hugo Kubinyi, BASF AG, Ludwigshafen, Germany October 1997
Gerd Folkers, ETH Zürich, Switzerland
Yvonne C. Martin, Abbott Laboratories, Abbott Park, IL, USA