Table Of ContentContributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
N. Claude Cohen )1( Ciba-Geigy Limited, Pharmaceuticals Division, CH-
4002 Basel, Switzerland
Peter Gund (219) Molecular Simulations Incorporated, Burlington, Massa-
chusetts 01803
Tamara Gund (55) New Jersey Institute of Technology, Newark College of
Engineering, Biomedical Engineering Program, Department of Chemistry,
Newark, New Jersey 07102
Roderick .E Hubbard (19) Department of Chemistry, University of York,
Heslington, York 10Y 5DD, United Kingdom
Akiko Itai (93) Laboratory of Medicinal Molecular Design, Faculty of Phar-
maceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113,
Japan
Konrad .F Koehler (235) Department of Medicinal Chemistry, Istituto id
Ricerche id Biologia Molecolare (IRBM), 00040 Pomezia, Roma, Italy
Gerald Maggiora (219) Upjohn Laboratories, Kalamazoo, Michigan 49001
xi
llX ~ Contributors
Yoshihiko Nishibata (93) Laboratory of Medicinal Molecular Design, Fac-
ulty of Pharmaceutical Sciences, ehT University of Tokyo, Bunkyo-ku,
Tokyo 113, Japan
.C Gregory Paris (139) Research Division, Ciba-Geigy Pharmaceuticals,
Summit, New Jersey 07901
John .P Priestle (139) Ciba-Geigy Limited, Pharmaceuticals Division, CH-
4002 Basel, Switzerland
Shashidhar N. Rao (235) Drug Design Section, Searle Research and Develop-
ment, Skokie, Illinois 60025
James .P Snyder (219, 235) Emerson Center for Scientific Computation,
Department of Chemistry, Emory University, Atlanta, Georgia 30322
J. .P ToUenaere (337) Department of Theoretical Medicinal Chemistry,
Janssen Pharmaceutica, B-2340 Beerse, muigleB
Nobuo Tomioka (93) Laboratory of Medicinal Molecular Design, Faculty
of Pharmaceutical ,secneicS The University of Tokyo, Bunkyo-ku, Tokyo
113, Japan
Miho Yamada Mizutani (93) Laboratory of Medicinal Molecular Design,
Faculty of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-
ku, Tokyo 113, Japan
I mill
Preface
Molecular modeling has become a well-established discipline in pharma-
ceutical research, - It has created unprecedented opportunities for assisting
the medicinal chemist in the rational design of new therapeutic agents. This
book si intended to be a guide for advanced students and chemists who are
entering the field of molecular modeling. It elucidates the important role
this research area si assuming in the understanding of the three-dimensional
(3-D) aspects of drug-receptor interactions at the molecular level.
Advances in computer hardware and software and in theoretical medici-
nal chemistry have brought high-performance computing and graphic tools
within the reach of most academic and industrial laboratories, thus facilitat-
ing the development of useful approaches to rational drug design. This book
provides the reader with the basic background necessary to approach such
systems. The discipline has various aspects, i.e., computer software and
hardware, structural and quantum chemistry, structure-activity relation-
ships, force-field simulations, superimposition techniques, 3-D database
searching, etc., which we have presented ni a unified way.
Our central aim was to provide a comprehensive overview of the strate-
gies currently used in computer-assisted drug design, such as pharmaco-
phore-based and structure-based drug design.
xiv ecaferP
The reader of this book will find not only the fundamental concepts
(the molecular basis of drug action, molecular simulations, molecular mim-
icry, etc.), but also ways of applying them to real problems. Although it si
not necessary to read the book strictly in chapter order, this may be preferred
as there si some progression in technicalities as the subject si developed.
The first chapter places the field in perspective, whereas Chapter 2
presents the molecular modelist's "panoply" of modeling hardware and
software equipment. Chapter 2 covers the areas of computer graphic basic
operations that are common to all molecular modeling applications. More
specialized aspects such as molecular mechanics and dynamics, the 3-D
representation of various molecular properties, and methods for deriving
bioactive conformations are introduced in Chapter 3. Manual docking has
been used extensively in a number of projects and has contributed to the
creation of sophisticated automated treatments, as presented in Chapter 4.
This chapter shows how tailor-made molecules can be identified either by
construction methods or by extraction from a 3-D database. The most
important experimental techniques for obtaining relevant 3-D information
on small molecules and proteins, namely X-ray crystallography and nuclear
magnetic resonance spectroscopy, are discussed in the first part of Chapter
5, whereas the second part presents 3-D databases and current techniques
used in database searching approaches. Chapter 6 gives an overview of
the current practice of computer-aided drug discovery and development. It
includes useful tables with some examples of successful use of molecular
modeling for drug discovery, and discusses the accuracy of current computa-
tional methods. In addition, organizational considerations concerning the
reporting relationships of molecular modeling groups in the pharmaceutical
industry are presented. Chapter 7, on drug-receptor interactions, shows
how it si possible to take full advantage of the knowledge of the 3-D structure
of the target protein in the design of drugs rationally conceived on the basis
of their complementarity with the target macromolecule. The book closes
with a glossary of more than 100 terms currently used in the field.
More and more medicinal chemistry publications contain substantial
molecular modeling analyses. Students and chemists often encounter diffi-
culties in learning the principles of modeling. Available review articles are
not sufficient and are either too specialized or too general. Likewise, available
books in the field generally are those of scientific proceedings and appear
as mere collections of chapters cataloging what has been presented. The
intent of this book is to fill this gap by providing advanced students and
chemists with the very information they need to learn the fundamental
concepts of molecular modeling, and enabling them to understand and apply
these concepts in their current research.
N. Claude Cohen
I
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Modeling
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.I DEFINITION OF MOLECULAR MODELING
Medicinal chemists today are facing many complicated challenges. The
most demanding and perhaps the most rewarding one si the rational design
of new therapeutic agents for treating human disease. For many years the
strategy for discovering new drugs consisted of taking a lead structure and
developing a chemical program for finding analog molecules exhibiting the
desired biological properties. Generally found by chance observation or by
random screening, initial lead compounds also encompassed, in the last
decade, the natural ligand of the system concerned. The process involved
several trial and error cycles patiently developed and analyzed by medicinal
chemists utilizing their experience and chemical intuition to ultimately select
a candidate analog for further development. The entire process si laborious,
expensive, and, perhaps when looked at today, conceptually inelegant. How-
ever, the undeniable fact si that this process has provided most of the existing
medications that are used today for indications ranging from the treatment
of minor pain to life-threatening diseases. The traditional methods of drug
discovery are now being supplemented by more direct approaches made
possible by the understanding of the molecular processes involved in the
underlying disease. In this perspective, the starting point in drug design si
Guidebook on Molecular Modeling ni Drug Design
Copyright (cid:14)9 1996 by Academic Press, Inc. llA rights of reproduction in any form reserved.
2 .N Claude Cohen
the molecular target (receptor, enzyme) in the body instead of the existence
of an already known lead structure.
The scientific concepts underlying this approach have been understood
for generations, but their practical application was beyond the reach of
existing technology. The existence of receptors and the lock-and-key con-
cepts currently considered in drug design were formulated by .P Ehrlich
(1909) and .E Fischer (1894). It was only in the seventies that it became
possible to understand some of the subtleties of the mechanisms involved
ni life processes. Pure samples of protein targets were isolated and X-ray
crystallography revealed their molecular architecture. It then became possi-
ble to learn how precisely three-dimensional (3-D) structures control the
regulation of life processes. In order to further such progress, a rational
approach to drug discovery has emerged in the pharmaceutical industry
and has contributed to the rapid development of molecular modeling as a
full discipline.
The concepts used in 3-D drug design are quite simple. New molecules
are conceived either on the basis of similarities with known reference struc-
tures or on the basis of their complementarity with the 3-D structure of
known active sites. Molecular interactions are regulated by subtle recogni-
tion and discrimination processes whereby the 3-D features and the binding
energies play an important role. Molecular modeling si a discipline that
contributes to the understanding of these processes in a qualitative and
sometimes quantitative way. It not only presents means for analyzing the
details of the molecular machinery involved in a known system and under-
standing the way the biological system functions, but it also provides the
necessary tools for predicting the potential possibilities of prototype candi-
date molecules. Molecular modeling can be simply considered as a range
of computerized techniques based on theoretical chemistry methods and
experimental data that can be used either to analyze molecules and molecular
systems or to predict molecular and biological properties.
The techniques currently available provide extensive insight into the
precise molecular features that are responsible for the regulation of biological
processes: molecular geometries, atomic and molecular electronic aspects,
and hydrophobic forces. llA these structural characteristics are of primary
importance in the understanding of structure-activity relationships and in
rational drug design.
The field has grown rapidly since the 1980s. A number of spectacular
advances have been made in molecular biology and in experimental and
theoretical structural chemistry as well as in computer technologies. They
lla constitute important elements of the molecular modeling framework.
The discipline si now fully recognized and integrated in the research process.
In the past the emergence of this new discipline had occasionally encountered
some opposition here and there. Nowadays, the science si mature and there
1 Molecular Modeling Perspective 3
si a growing number of success stories that continuously expand the armory
of drug research.
.II EHT FIRST GENERATION OF RATIONAL APPROACHES IN
DRUG DESIGN
Rational drug design si based on the principle that the biological proper-
ties of molecules are related to their actual structural features. What has
changed along the years si the way molecules are perceived and defined. In
the early 1970s, medicinal chemists considered molecules as mere topological
two-dimensional (2-D) entities with associated chemical and physicochemi-
cal properties. Quantitative structure-activity relationships (QSAR) con-
cepts began to be considered and became very popular. It was implemented
in computers and constituted the first generation of computer-aided rational
approaches in drug design. This discipline was promoted by Hansch and
his group (Fujita, 1990). It was based on the determination of mathematical
equations expressing the biological activities in terms of molecular parame-
ters such as log P (the partitioncoefficient), steric substituent constants (Es),
molar refractivity (MR) (Fujita, 1990). This has been expanded to the use of
structural indexes obtained by quantum mechanical treatments (i.e., HOMO
and LUMO energies, total dipole moments, charge and hybridization mo-
ments, molecular polarizability, Mulliken electronegativity, and frontier or-
bital indices).
Such methods have dominated the area of medicinal chemistry since
the 1980s. Looking back now, one can notice that they have proven to be
useful only for the optimization of a given series. Being constructed on a
fixed (therefore invariant) 2-D formula, these approaches were unable to
go beyond the 2-D frame of the structure considered. This has been a great
limitation for those interested in lead finding. It si worth noticing that, in
general, most of the parameters defined in QSAR approaches are conceptu-
ally relevant and not very different from those currently used today in
molecular modeling (e.g., steric parameters, electronic indexes, hydrogen
bonding capabilities, and hydrophobicities). However, most of these proper-
ties have not been well represented by the simplistic numerical parameters
considered to represent these features: the interactions between a ligand and
a protein require much more detailed information than the ones included
in substituent indexes characterizing the molecular properties. The second
generation has shown that consideration of the full detailed properties in
3-D si necessary in allowing the subtle stereochemical features to be ap-
preciated.
In fact, the increasing interest elicited by molecular modeling in the
mid-1980s was a direct consequence of the limitations that were found in
4 .N Claude Cohen
the QSAR approaches by those attempting to find lead compounds. Not
only were QSAR methods lli suited for that, they were also used more often
for retrospective analyses than for predictive undertakings.
III. MOLECULAR MODELING: EHT SECOND NOITARENEG
.A Conceptual Frame and Methodology of Molecular Modeling
In molecular modeling the perspective si no longer restricted, as it was in
the past, to the design of closely related analogs of known active compounds.
Molecular modeling has opened the way to the discovery of lead structures
by a rational approach, and its central role in rational drug design has
become fully apparent.
The acceptance by medicinal chemists of molecular modeling was fa-
vored by the fact that the structure-activity correlations are represented by
3-D visualizations of molecular structures and not by mathematical equa-
tions. The latter do not exactly correspond to the natural way of representing
chemical systems. The 3-D representations have improved the perception
of the chemists and have contributed to expanding their current chemical
intuition. Moreover, looking at a drug in 3-D actually does give the impres-
sion of knowing everything about it, including its biological properties. Not
so far from this intuition, molecular modeling perceives biological function
as being embedded in the 3-D structure of the molecules. From that point of
view, the "lock and key" complementarity between a drug and its biological
receptor suggested in the early 1900s si literally considered.
Along these lines, the biological activity of drugs si to be recognized
in their actual 3-D molecular features. Computer-aided molecular design
(CAMD) si expected to contribute to the discovery of "intelligent" molecules
conceived on the basis of precise three-dimensional stereochemical consider-
ations.
"Direct" and "indirect" designs are the two major modeling strategies
currently used in the conception of new drugs. In the first approach the
three-dimensional features of a known receptor site are directly considered
whereas in the latter the design si based on the comparative analysis of
the structural features of known active and inactive molecules that are
interpreted in terms of their complementarity with a hypothetical receptor
site model (Fig. .)1
.B The Field Currently Covered
Molecular modeling has widened the horizons of pharmaceutical re-
search by providing tools for finding new leads. The fields currently covered
by this discipline include:
1 Molecular Modeling Perspective 5
Conceptual frame used ni molecular modeling
and drug design
Molecular Modeling Analyses
I i
Small molecule l Macromolecular 1
modeling ! modeling
l I
i "i.an~ 1
o M~ sets
f small molecules fit analyses
tceridnI( gurd )ngised tceriD( gurd )ngised
I I
- Design of molecules conforming i
to the desired requirements J
ERUGIF I lautpecnoC emarf ni dedia-retupmoc drug .ngised
(cid:12)9 Direct drug design: the three-dimensional features of the receptor site
(i.e., known X-ray structure or 3-D model of a receptor) are directly consid-
ered for the design of lead structures.
(cid:12)9 Indirect drug design: the analysis si based on the comparison of the
stereochemical and physicochemical features of a set of known active/inac-
tive molecules; lead structures are designed on the basis of the pharmaco-
phore model obtained by such analyses.
(cid:12)9 Database searches: lead compounds are identified from searches using
databases defined in 3-D. The input query describes the pharmacophore; it
consists of a set of molecular fragments together with their relative location
in 3-D and additional structural constraints (geometrical or chemical).
(cid:12)9 Three-dimensional automated drug design: new lead compounds are
generated by the computer on the basis of a "growing" procedure inside
the active site of a protein whose 3-D structure si known or by a computerized
treatment by assembling a set of pharmacophoric fragments defined in 3-D.
(cid:12)9 Molecular mimicry: lead molecules are conceived as mimics of a
known reference compound as, for example, the design of mimics of selected
peptide ligands.
Each of the areas just mentioned has been developed in the different chapters
of this book.
C. Importance of the "Bioactive Conformation"
The existence of an experimental structure for the protein-ligand com-
plex allows one to use this information to design new molecules. The knowl-
edge of the bioactive conformation of the ligand as it binds to the receptor
or enzyme si of great utility in designing new mimic molecules that are
potent and specific.
6 .N Claude Cohen
Experience shows that the bioactive conformation of a molecule si not
necessarily the one found in solution or in the crystal. Rather it si the specific
conformation of the lowest energy in the context of the receptor. Knowing
how the ligand si oriented in the binding pocket si also extremely valuable
in designing new structures. The chemist tries to design a better analog of
the existing prototype structure on which he si working or a completely
new chemical structure. Typical questions include: What are the possibilities
for increasing potency? Where can hydrophobic groups be added so that
they penetrate well into hydrophobic pockets? Which hydrogen bond can
be created between the ligand and the protein to improve selectivity? Where
can polar groups be added in the prototype molecule that will strengthen
the binding energy of the compound? Will this steric contact be favorable
to the binding of the molecule? Can another binding mode be considered
for the compound? Will this side chain of the protein be able to move? is
this modification of the prototype candidate molecule energetically favorable
for its internal energy? sI this polar group "happy" in this subpocket? By
providing answers to such questions the molecular modeling approach
allows full utilization of the structural information and capitalizes on what
si known about the mechanism of action of the protein-ligand complex.
.VI MOLECULAR MIMICRY AND LARUTCURTS SEITIRALIMIS
A. Molecular Mimicry
Molecular mimicry si an activity of central importance in drug research.
Very often the molecules that are created are conceived as mimics of sub-
stances known to interact with the biological system considered (i.e., hor-
mones, peptides, and transmitters). For example, peptidomimetic molecules
are conceived to mimic the structure of an endogenous peptide and are
converted into a regular organic molecule. The reason si that very often
peptide molecules cannot be developed as drugs. In general, peptide mole-
cules are:
(cid:12)9 biologically unstable
(cid:12)9 poorly absorbed
(cid:12)9 rapidly metabolized.
A nonpeptide molecule should permit one to overcome these drawbacks.
It si expected that the synthetic molecules may provide the structural diversity
necessary to allow the molecule to be optimized for:
(cid:12)9 specificity
(cid:12)9 oral bioavailability
(cid:12)9 pharmacokinetic properties
Molecular mimicry can be considered from various points of view and
can cover many molecular properties. Actually, this si not really a new
