Chemoinformatics: Concepts, Methods, and Tools for Drug Discovery

529 Pages·2004·4.383 MB·English

by  Gerald M. Maggiora, Veerabahu Shanmugasundaram (auth.), Jürgen Bajorath (eds.)

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Chemoinformatics
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M E T H O D S I N M O L E C U L A R B I O L O G YTM
Chemoinformatics
Concepts, Methods,
and Tools for Drug Discovery
Edited by
Jürgen Bajorath
Albany Molecular Research Inc.
Bothell Research Center, Bothell, WA
and University of Washington, Seattle, WA
Humana Press Totowa, New Jersey
iv
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Chemoinformatics : concepts, methods, and tools for drug discovery / edited by Jürgen Bajorath.
p. cm. — (Methods in molecular biology ; v. 275)
Includes bibliographical references and index.
ISBN 1-58829-261-4 (alk. paper) eISBN 1-59259-802-1
1. Chemoinformatics. I. Bajorath, Jürgen. II. Series: Methods in
molecular biology (Clifton, N.J.) ; v. 275.
RS418.C48 2004
615'.19—dc22 2004047477
v
Preface
In the literature, several terms are used synonymously to name the topic
of this book: chem-, chemi-, or chemo-informatics. A widely recognized defi-
nition of this discipline is the one by Frank Brown from 1998 (1) who defined
chemoinformatics as the combination of “all the information resources that a
scientist needs to optimize the properties of a ligand to become a drug.” In
Brown’s definition, two aspects play a fundamentally important role: deci-
sion support by computational means and drug discovery, which distinguishes
it from the term “chemical informatics” that was introduced at least ten years
earlier and described as the application of information technology to chem-
istry (not with a specific focus on drug discovery). In addition, there is of
course “chemometrics,” which is generally understood as the application of
statistical methods to chemical data and the derivation of relevant statistical
models and descriptors (2). The pharmaceutical focus of many developments
and efforts in this area—and the current popularity of gene-to-drug or simi-
lar paradigms—is further reflected by the recent introduction of such terms
as “discovery informatics” (3), which takes into account that gaining knowl-
edge from chemical data alone is not sufficient to be ultimately successful
in drug discovery. Such insights are well in accord with other views that the
boundaries between bio- and chemoinformatics are fluid and that these dis-
ciplines should be closely combined or merged to significantly impact bio-
technology or pharmaceutical research (4). Clearly, from an algorithmic or
methodological point of view, bio- and chemoinformatics are much more
similar to each other than many of their applications would suggest, at least
on a first glance. It is fair to assume that the application of information sci-
ence and technology to chemical or biological problems will further develop
and mature, as well as continue to define, and redefine, itself.
If we wish to focus on chemoinformatics in a more narrow sense, what
should we really consider? First, methods that support decision making in the
context of pharmaceutical research (2) (such as compound design and selec-
tion) or methods that help interfacing computational and experimental pro-
grams (4) [such as virtual and biological screening (5)] are without doubt
essential components. Second, equally important to developing methods and
research tools is building and maintaining computational infrastructures to
collect, organize, manage, and analyze chemical data. Third, I would propose
v
vi Preface
that it has also become increasingly difficult to distinguish between chemoin-
formatics and chemometrics, since statistical methods, models, and descrip-
tors play a crucial role in, for example, similarity and diversity analysis or
virtual screening. Fourth, approaches to explore (and exploit) structure–activ-
ity or structure–property relationships can hardly be excluded from chemoinfor-
matics research, much of which aims at helping to identify or make better molecules.
This means that approaches that are long disciplines in their own right such as QSAR
or structure-based design can—and perhaps should—also be considered to contrib-
ute and belong to chemoinformatics. Lastly, evaluation of drug-likeness and predic-
tion of downstream ADME characteristics of compounds have become highly
relevant topics for chemoinformatics and drug discovery research and are approached
using rather different concepts and algorithms.
Being confronted with the task of putting Chemoinformatics: Concepts,
Methods, and Tools for Drug Discoverytogether, I decided to focus on authors
and their individual contributions, rather than trying to address everything pos-
sible that could be covered under the chemoinformatics umbrella, as discussed
above. It was my sincere hope that this approach would do justice to this still
evolving and rather diverse field. Therefore, a variety of researchers (including
well-recognized pioneers, senior scientists, and junior-level investigators) from
diverse professional environments (academia, large pharmaceutical industry,
and biotech companies) were asked to contribute. Chemoinformatics-relevant
subject areas were initially outlined to provide some guidance, but authors
were given as much freedom as possible in choosing their topics and design-
ing their chapters. The result we are looking at is the rather diverse array of
chapters I had initially hoped for. Certainly, many chapters go well beyond
the introduction of single methods and protocols that is a major theme of the
Methods in Molecular Biologyseries, at least as far as experimental science is
concerned. Our contributions range from the description of specific methods
or applications to the discussion of fundamentally important concepts and
extensive review articles. On the other hand, some of the topics I initially
envisioned to cover are missing, for example, neural network simulations or
chemical genetics, to name just two. By contrast, some contributions present
and discuss similar methods, for example, compound selection or library
design, in rather different ways, which I find particularly interesting and stimu-
lating.
Chemoinformatics: Concepts, Methods, and Tools for Discoverybegins
with an elaborate theoretical discussion of the concept of molecular similarity
by Maggiora & Shanmugasundaram that is one of the origins and cornerstones
of chemoinformatics as we understand it today. Chapter 2 by Willett follows
up on this theme and extends the discussion to molecular diversity, a related
Preface vii
—yet distinct—and equally fundamental concept. Following these method-
ologicalconsiderations, Bembenek & colleagues describe a computational infra-
structure to enable pharmaceutical researchers to efficiently access basic
chemoinformatics tools and help in decision-making. Chapters 4 and 5 by Parker
& Schreyer and Lajiness & Shanmugasundaram describe efforts to interface
chemoinformatics approaches with high-throughput screening and with screening
and medicinal chemistry, respectively. As discussed above, the formation of such
interfaces is one of the major challenges—and opportunities—for chemoinfor-
matics in pharmaceutical research.
Esposito & colleagues provide an extensive discussion of QSAR approaches
in Chapter 6. The authors review basic principles and methods and then focus on
the latest developments in multidimensional QSAR analysis. In the following chap-
ter,Gomar&colleagues describe the development of a lipophilicity descriptor that
alleviates the molecular alignment problem in QSAR and discuss exemplary appli-
cations. In general, the majority of chemoinformatics applications critically depend
on the use of descriptors of molecular structure and properties, and Chapter 8 by
Labute presents a good example of descriptor design. The author describes the gen-
eration of a novel class of molecular surface property descriptors that can be readily
calculated from 2D representations of molecular structures.
The next four chapters focus on partitioning algorithms and classification
methods that have become very popular for the analysis of large compound
databases, screening sets, and virtual screening for active molecules. Xue &
colleagues describe cell-based partitioning based on principal component analysis
and, to contrast with chemical space dimension reduction methods, Godden &
Bajorath introduce a statistically based partitioning algorithm that directly oper-
ates in higher-dimensional, albeit simplified, chemical descriptor spaces. In the
following back-to-back chapters, Lam & Welch first apply clustering and cell-
based partitioning methods for the selection of active compounds from the HIV
data set of the National Cancer Institute. Based on their computational scheme
and results, Young & Hawkins apply recursive partitioning (another statistical
approach) to the same data set, thus enabling direct comparisons.
Following these compound classification and selection methods, Chap-
ters 13–15 describe different approaches to compound library design. Gillet
discusses a genetic algorithm-based method to simultaneously optimize mul-
tiple objectives or properties when designing libraries. Schnur & colleagues
describe various approaches to focus compound libraries on families of thera-
peutic targets, which represents a major trend in drug discovery, and Zheng
introduces simulated annealing as a stochastic approach to library design.
In Chapter 16, Lavine & colleagues return to a compound classification prob-
lem by using a combination of principal component analysis and a genetic algo-
viii Preface
rithm that is here applied to an optimization problem different from the one dis-
cussedbyGillet. In the next chapters, Crippen introduces novel ways of describ-
ing molecular chirality and conformational parameters with relevance for the
analysis of structure–activity relationships, and Pick provides a brief review of
scoring functions for structure-based virtual screening. The book ends with an
extensive and detailed description by Jalaie & colleagues of different types of
methods, including structure-based approaches, to predict drug-like character
of compounds and basic ADME properties based on modeling their putative
interactions with cytochrome P450 isoforms, which are important drug metabo-
lizing enzymes. This discussion complements other major themes represented
herein including molecular similarity, structure-activity relationships, and com-
pound classification and design.
First and foremost, I would like to thank our authors whose diverse con-
tributions have made this project a (hopefully, interesting!) reality.
Jürgen Bajorath
References
1. Brown, F. K. (1998) Chemoinformatics: What is it and how does it impact drug
discovery.Ann. Rep. Med. Chem.33, 375–384.
2. Goodman, J. M. (2003) Chemical informatics. Chem. Inf. Lett.6 (2);
http://www.ch.cam.ac.uk/MMRG/CIL/cil_v6n2.html#14
3. Claus, B. L. and Underwood, D. J. (2002) Discovery informatics: Its evolving
role in drug discovery. Drug Discov. Today7, 957–966.
4. Bajorath, J. (2001) Rational drug discovery revisited: Interfacing experimental
programs with bio- and chemo-informatics. Drug Discov. Today6, 989–995.
5. Bajorath, J. (2002) Integration of virtual and high-throughput screening. Nature
Rev. Drug Discov.1, 882–894.
ix
Contents
Preface .............................................................................................................v
Contributors.....................................................................................................xi
1 Molecular Similarity Measures
Gerald M. Maggiora and Veerabahu Shanmugasundaram..............1
2 Evaluation of Molecular Similarity and Molecular Diversity Methods
Using Biological Activity Data
Peter Willett..........................................................................................51
3 A Web-Based Chemoinformatics System for Drug Discovery
Scott D. Bembenek, Brett A. Tounge, Steven J. Coats,
and Charles H. Reynolds................................................................65
4 Application of Chemoinformatics to High Throughput Screening:
Practical Considerations
Christian N. Parker and Suzanne K. Schreyer.................................85
5 Strategies for the Identification and Generation of Informative
Compound Sets
Michael S. Lajiness and Veerabahu Shanmugasundaram...........111
6 Methods for Applying the Quantitative Structure–Activity
Relationship Paradigm
Emilio Xavier Esposito, Anton J. Hopfinger,
and Jeffry D. Madura.....................................................................131
7 3D-LogP:An Alignment-Free 3D Description of Local Lipophilicity
for QSAR Studies
Jérôme Gomar, Elie Giraud, David Turner, Roger Lahana,
and Pierre Alain Carrupt...............................................................215
8 Derivation and Applications of Molecular Descriptors Based
on Approximate Surface Area
Paul Labute.........................................................................................261
9 Cell-Based Partitioning
Ling Xue, Florence L. Stahura, and Jürgen Bajorath...................279
10 Partitioning in Binary-Transformed Chemical Descriptor Spaces
Jeffrey W. Godden and Jürgen Bajorath........................................291
ix
x Contents
11 Comparison of Methods Based on Diversity and Similarity for
Molecule Selection and the Analysis of Drug Discovery Data
Raymond L. H. Lam and William J. Welch......................................301
12 Using Recursive Partitioning Analysis to Evaluate Compound
Selection Methods
S. Stanley Youngand Douglas M. Hawkins....................................317
13 Designing Combinatorial Libraries Optimized
on Multiple Objectives
Valerie J. Gillet...................................................................................335
14 Approaches to Target Class Combinatorial Library Design
Dora Schnur, Brett R. Beno, Andrew Good,
and Andrew Tebben......................................................................355
15 Simulated Annealing: An Effective Stochastic Optimization
Approach to Computational Library Design
Weifan Zheng.....................................................................................379
16 Genetic Algorithms for Classification of Olfactory Stimulants
Barry K. Lavine, Charles E. Davidson, Curt Breneman,
and William Kaat............................................................................399
17 How to Describe Chirality and Conformational Flexibility
Gordon M. Crippen............................................................................427
18 Novel Scoring Methods in Virtual Ligand Screening
Daniel Pick..........................................................................................439
19 Prediction of Drug-like Molecular Properties:
Modeling Cytochrome P450 Interactions
Mehran Jalaie, Rieko Arimoto, Eric Gifford,
Sabine Schefzick, and Chris L. Waller.......................................449
Index............................................................................................................521