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History and Evolution of the Pharmacophore Concept in Computer-Aided Drug

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 Current Topics in Medicinal Chemistry 2002, 2, 1321-1332 1321

History and Evolution of the Pharmacophore Concept in Computer-Aided

Drug Design

Osman F. Güner*

Accelrys Inc., 9685 Scranton Road, San Diego, CA 92121, USA

Abstract: With computer-aided drug design established as an integral part of the lead
discovery and optimization process, pharmacophores have become a focal point for
conceptualizing and understanding receptor-ligand interactions. In the structure-based
design process, pharmacophores can be used to align molecules based on the three-
dimensional arrangement of chemical features or to develop predictive models (e.g., 3D-
QSAR) that correlate with the experimental activities of a given training set.
Pharmacophores can be also used as search queries for retrieving potential leads from
structural databases, for designing molecules with specific desired attributes, or as
fingerprints for assessing similarity and diversity of molecules. This review article
presents a historical perspective on the evolution and use of the pharmacophore concept in the pharmaceutical,
biotechnology, and fragrances industry with published examples of how the technology has contributed and
advanced the field.

INTRODUCTION HISTORY

“Perceiving a pharmacophore is the most important first
step towards understanding the interaction between a receptor
and a ligand.” The first sentence from the preface of the
pharmacophore book [1] highlights the importance of the
concept of pharmacophore in drug design. Modern definition
of pharmacophore represents the three-dimensional
arrangement of chemical features in a molecule that is
responsible for its biological activity. Today, pharmacophore
is considered a critical aspect of discovery, design, and
optimization of drug candidates.
While there are no recent review articles written
specifically on the topic of pharmacophores, there are several
review articles written for three-dimensional (3D) database
searching where the concept of pharmacophores were covered
in part as they represent effective search queries for 3D
databases. Van Drie’s monolog published on the Internet
represents an early review [2] of 3D-searching and
pharmacophore technologies. Güner and Henry published the
first detailed review on 3D searching and pharmacophores in
Encyclopedia of Computational Chemistry [3]. The
pharmacophore book [1] covers, rather comprehensively, the
evolution of the technology and the state-of-the-art until mid
1999. More recently, Kurogi and Güner published a review
in Current Medicinal Chemistry that not only covers the
theory, but also reports successes in pharmacophores and 3D
searching with the Catalyst software [4].
Pharmaceutical industry has started during 1880-1930
period where chemical companies established research
laboratories to develop new drugs, isolated active chemicals
from natural products, and tested them for biological activity
[5]. The earliest use of the concept of pharmacophore goes
back to the end of nineteenth century; Paul Ehrlich during
his M.D. thesis research, discovered that methylene blue
selectively attached to nerve fibers (he was trying to stain
bacteria to make them visible under microscope). Following
with this observation, Ehrich’s developed the ideas for
experimental therapeutics (infecting laboratory animals and
systematically study the effects of various chemical
substances) and chemotherapy (the process of synthesizing
and testing as many derivatives of promising chemicals as
possible for biological effect) [5]. Paul Ehrlich’s shift of
focus from chemical dye research into a systematic chemical
search for biological effect marks the beginning of the use of
pharmacophore concept: a molecular framework that carries
(phoros) the essential features responsible for a drug’s
(pharmacon) biological activity [1]. Hence, Paul Ehrlich is
credited to be the first scientist to conceptualize
pharmacophores [6]. Ehrlich’s early definition of
pharmacophore is remarkably unperturbed for over 90 years.
Hoechst sponsored some of Ehrilch’s studies that culminated
with the discovery and development of a cure for syphilis,
drug released in 1910 under the trade name Salvarsan. With
this success Ehrilch achieved credibility to his ideas on
experimental therapeutics and chemotherapy, which formed
the basis of scientific and systematic study of drug
candidates.

A very good description of the early days and evolution

of the pharmacophore concept is published by Peter Gund
*Address correspondence to this author at the Accelrys Inc., 9685
[7], who is also the author of the modern definition of
Scranton Road, San Diego, CA 92121, USAe-mail: osman@accelrys.com
pharmacophore as “a set of structural features in a molecule

1568-0266/02 $35.00+.00 © 2002 Bentham Science Publishers Ltd.

1322 Current Topics in Medicinal Chemistry, 2002, Vol. 2, No. 12
that is recognized at a receptor site and is responsible for that
molecule’s biological activity” [8, 9]. This work was shortly
followed by a brief review by Humblet and Marshall [10].
With respect to first computer program to recognize
pharmacophore patterns, credit goes to Gund, Wipke, and
Langridge with software developed at Princeton University
called MOLPAT [11].
SOFTWARE TOOLS FOR PHARMACOPHORE
DEVELOPMENT
Following the initial development of MOLPAT in 1974,
nothing much happened in this field for about 15 years. One
of the reasons for lack of activity for so long was the need
for three-dimensional structural databases (significant
benefits of electronic pharmacophore models can be attained
through 3D-dabases searching and one could perform 3D-
Search only against 3D Databases). In the 1970’s there were
very few 3D databases available (one notable database of that
period was Cambridge Structural Database [12]). Once rapid
3D structure generation software became available during
1987-1989 (e.g., CONCORD [13], CORINA [14], AIMB
[15], WIZARD [16]) the demand for 3D-searching software
reached a critical level. Most of the companies in the
pharmaceutical industry have already been maintaining their
corporate structural databases in one form or another. With
the above tools, they could now convert their corporate
databases into 3D databases. Hence, mining 3D databases
became a critical technological advantage for these
companies.
Various academic institutions and software companies
started to work on developing such technologies; some
pharmaceutical companies did not want to wait for
commercial tools and developed their own in-house systems.
Examples for such in-house systems are ALADDIN [17] at
Abbott (later commercialized by Daylight) and 3D-Search
[18] at Lederle. Specialized 3D searching software were also
developed at various academic and government institutions
including CAST-3D at Chemical Abstract Services [19],
DOCK at University of California at San Francisco [20], and
CAVEAT at University of California at Berkeley [21].
Finally, 15 years after the development of MOLPAT, the
first commercial 3D searching system was released th
in late
1989 (MACCS-3D was released in December 15 of 1989,
and was the first product marketed by the author of this
review article) [22]. During the next four years, all of the
commercial 3D-searching technology that is available today
was developed (MACCS-3D [23] (was available from MDL,
now ISIS-3D is available from MDL), ChemDBS-3D [24]
(was available from Accelrys), UNITY [25] (currently
available from Tripos), and Catalyst [26] (currently available
from Accelrys).
Specialized pharmacophore development software
paralleled the evolution of 3D-searching technology. In fact,
the technologies are so closely related to each other, all of
the commercial 3D-searching software above included 3D
query generation tools that constitutes pharmacophore
models.
Osman F. Güner
Coming back to pharmacophores, Gund et al. developed
the first software for pharmacophore mapping [8, 9]. Around
the same time frame Garland Marshall developed the Active
analog concept [27]: identification of pharmacophores from
the intersection of conformational space of active molecules.
Similar to the evolution of the 3D-searching technology, the
critical demand for the pharmacophore development software
was reached shortly following the wide availability of 3D-
searching software in the early 90s. Most notable software
tools in this area are DISCO by Martin et al. [28] (available
from Tripos), HipHop by Barnum et al. [29] (available from
Accelrys), and GASP by Jones and Willett [30] (available
from Tripos). Meanwhile predictive pharmacophore models
were also developed based on statistical means (many of
which are referred to as 3D-QSAR approaches). The notable
predictive pharmacophore programs are CoMFA by Cramer
et al. [31] (available from Tripos), Apex-3D by Golander and
Vorpagel [32] (was available from Accelrys), and HypoGen
by Teig et al. (later published by Li et al [33], available
from Accelrys). Detailed usage and validation examples for
all of the pharmacophore development software above are
covered in the pharmacophore book [1].
THE ISSUE OF CONFORMATIONAL FLEXIBILITY
AND DYNAMIC PHARMACOPHORES
The early review articles from Gund and Humbet [8, 9],
[10] discusses rigorously the issue of conformational
flexibility for pharmacophores. Because pharmacophores
helped advance our thinking from topology (2-dimensional
connectivity between atoms) to topography (3-dimensional
arrangement of chemical features) lack of handling of
conformational flexibility has been a big obstacle for the
evolution of the pharmacophore technology. In fact, one of
the early commercial pharmacophore development programs,
namely the active analog approach, was entirely based on
constrained systematic conformational search approach [34].
In a recent review of active analog approach, Beusen and
Marshall discuss the evolution of the technology over the
years [35]. While the issue of conformational flexibility in
pharmacophores has occupied the interest of many scientists
in the 80s, at least one group provided an antagonistic
approach to the issue suggesting that conformational
searching does not necessarily improve the yield of active
compounds in 3D-database searches [36]. Nevertheless,
during the early 90s three independent solutions to the
ligand conformational flexibility problem emerged.
The conformational flexibility could be handled:
1. In the database, by generating and storing multiple
conformations within the database [37]. This
approach did not get much support early on due to
the difficulties in addressing questions like: how
many conformations to store? Is the bound
conformation represented in the database?
2. In the search query, by designing specialized
queries that handle the flexible parts of the
compounds differently [38]. This approach was not
very popular since it was placing the burden on the
user to develop smart queries.
History and Evolution of the Pharmacophore Concept
3. In the search process, by generating the
conformations on the fly, during the search process
[39, 25] (so called flexible searching).
The third approach has received a broad level of approval
as “the” solution for the conformational flexibility problem.
It involved storage of a single conformation in the database,
and performing a torsional “tweak” during the 3D-search in
attempt to fit the compound onto the pharmacophore query.
Both ISIS/3D [25] and Unity software systems [39] have
adopted this approach, whereas Catalyst adopted a
combination of the first and third approaches (see later). The
reason this approach (i.e., on-the-fly torsional tweak) did not
have the same performance limitations of the first approach
(i.e., storage of multiple conformations in the database) is
algorithmic. As opposed to generation of all possible
conformations up front, this approach ended up generating
much fewer conformations, approaching the actual solution
with each iteration (a conformation that will map to the
pharmacophore query), and stopping the conformational
exploration as soon as “a” conformation that matches the
pharmacophore is attained. While credited as the best
solution for this important problem, there were still two
limitations with this approach:
1. The computation time needed to perform the database
searches was much higher then the previous methods
(in method 1, for example, the search speeds were
faster because the cost of conformation generation was
accounted for during the database building process).
2. The more important limitation was the accuracy of
the results: a small percentage of valid hits will not
be recognized due to the local minima problem (i.e.,
a compound may converge into a conformation that
does not properly map onto a pharmacophore and get
rejected, whereas from a different starting point,
another conformation of the same compound may
have been mapped properly).
Eventually, the second problem was addressed in all
three of the commercial 3D searching programs: With the
ISIS/3D software, by giving a random kick to a molecule
before rejecting and then re-driving the torsion for a fit.
This, in a sense, resembled storing two conformations in the
database instead of one, which eliminated a significant part
of the “false negatives”. With Unity the users are provided
the option to define the number of attempts for the
algorithm to try a different conformation before giving up a
particular compound. The problem was more completely
solved in the Catalyst software, as the flexible fitting (so
called BEST algorithm) was already being performed on a
multi-conformation database. In addition, the conformational
search with BEST was being performed by driving the full
forces (bond distances, angles, and dihedral angels) of a
molecule as opposed to driving only the torsions (dihedral
angles).
While the conformational flexibility problem was
generally accepted as solved by the end of 1994. Smellie and
co-workers developed a new algorithm, so called “poling”
[40], that opts for generating diverse conformations of a
molecule until the entire conformational space is adequately
Current Topics in Medicinal Chemistry, 2002, Vol. 2, No. 12 1323
represented and conformational diversity is achieved [41,
42]. The term poling was based on the analogy that once a
local minimum energy conformation is established, a pole is
used to raise the potential energy hyperspace of the molecule
on the precise minimum energy point. As the surface at this
point is raised, the optimizer will not converge to the same
conformation again. After a number of conformations
generated and the surface have been raised with the same
number of poles, the conformation generation stops once the
hypersurface level exceeds the user-defined energy
maximum. This approach was not only able to generate
diverse conformations; it also ensured that conformational
space of the molecule is adequately covered. With this
development, it also became possible to revert back to the
first approach and perform rigid searches on a database with
multiple conformations generated with the poling approach.
Today Catalyst program provides both options to the
researcher: ability to perform a rigid or flexible search on a
multi-conformation database. The high level details of the
poling algorithm, as well as the rigid and flexible search
algorithms were described in a recent review by Kurogi and
Güner [4].
The conformational flexibility issue for ligands in
pharmacophore development and database searching seem to
have been resolved. However, the conformational flexibility
of the receptor active site is still an open issue. The concept
of “dynamic pharmacophores” is evolving to address some
of these issues. The earliest example for dynamic
pharmacophores was described by Güner and co-workers as
“flexible queries” as an interim solution for the ligand
conformational flexibility [38, 43]. Carlson and co-workers
have recently developed dynamic pharmacophores that
considers the conformational flexibility of the receptor
enzyme [44]. In this method, conformational flexibility of
an enzyme active site was monitored through a molecular
dynamics study and the changes in the conformational
flexibility of the enzyme was incorporated into the
pharmacophore model with respect to varying tolerances on
the pharmacophore features [45].
CONFORMATION DRIVEN PHARMACOPHORES
One of the early examples of conformation driven
pharmacophores involves the utilization of the active analog
approach [35]. A celebrated example is the application of
this approach to angiotensin-converting enzyme (ACE)
inhibitors by Mayer and co-workers [46], and later by
Dammkoehler and co-workers [47]. In cases where the
receptor enzyme information is not available, conformation
driven pharmacophores still provide valuable opportunity to
identify potential active compounds (ligand based design).
Recently, Van Drie has also developed conformation-based
strategies for constructing pharmacophores [48] with a new
focus on improving selectivity. Van Drie proposes to
achieve higher selectivity by applying a so-called “shrink-
wrap” to a series of active compounds at their putative
bound conformations. A recent review by Ghose and
Wendoloski cover the conformation-based pharmacophore
approaches quite well [49]. Fig (1) shows how a modern
pharmacophore looks like (together with a compound that
1324 Current Topics in Medicinal Chemistry, 2002, Vol. 2, No. 12 Osman F. Güner

Fig. (3). A pharmacophore model is proposed for the

anticipated hydrogen bonding and lipophilic interactions
based on the bound conformation of methotrexate.
Fig. (1). A selective COX-2 inhibitor is mapped onto the
pharmacophore model (credit: Shashidhar Rao, unpublished pharmacophores were reserved for only ligand-based
results). approaches, in those cases where the receptor structure was
not readily available. Utilization of a receptor active site to
fits to the model). In this case, a selective COX-2 inhibitor develop a pharmacophore model is a relatively recent
was retrieved with this pharmacophore via a database search. activity. Clark and co-workers developed some
Blue and cyan spheres represent aliphatic and aromatic
hydrophobic groups, the orange spheres represent aromatic
ring planes, and the green spheres represent the hydrogen
bond acceptors. The cone indicates the direction of the
hydrogen bond and the tip of the cone is where the receptor
hydrogen-bonding site is expected.

RECEPTOR-BASED PHARMACOPHORES

First application of receptor active site information in

database searching was done through the DOCK program
[20]. This program may also be considered the earliest
virtual high-throughput screening program. DOCK and
several other de novo design programs are used to ascertain
the complementarities of the receptor active site in use for Fig. (4). Alternative pharmacophore model proposed based on
either database searching or building or designing new the same methotrexate-DHFR complex.
compounds within the active site. In the early days, use of computational tools for generating pharmacophores from
active sites and performing database searches with these
pharmacophores [50].

Fig. (2). A close up look at the active site of dihydrofoloate

reductase with a bound ligand (methotrexate) [4dfr].
Fig. (5). The pharmacophore model displayed in Fig (3) is
Highlighted is possible hydrogen bonding interactions
enhanced with the shape of the bound conformation of
between methotrexate and the receptor, with distances shown in
methotrexate.
Angstroms.
History and Evolution of the Pharmacophore Concept
The bound conformation of a ligand can form the basis
of a pharmacophore. Fig (2) displays a close up look at the
dihydrofolate reductase active site with methotrexate
complex (based on X-Ray structure - Protein Data Bank
4dfr). Clearly, the bound conformation of methotrexate
provides exceptional opportunities for developing a detailed
and accurate pharmacophore model. However, which
hydrogen-bond donor should be used (see Fig. (2))? The one
with isoleucine-5 or isoleucine-94? Similarly, should the
interaction with aspartate-27 be through a hydrogen-bond
donor, or acceptor? Fig (3) and Fig (4) displays two
alternative pharmacophore models. Both of these models,
when used to search 3D databases will retrieve hits that
constitute potential active ligands, yet they clearly represent
alternative binding modes. It is important to understand that
when building a pharmacophore model from receptor active
site, there is a potential to generate hundreds to thousands of
models. These models will then need to be analyzed and
prioritized. Existing de novo design technologies such as
Ludi [51] can be leveraged to develop and analyze the
receptor active site and such information can be converted
into a series of pharmacophores. One such commercial
product that utilizes this concept is the structure-based
focusing (SBF) module of Cerius2 [52]. Application of this
technology to estrogen receptor [53] and 17B-hydroxysteroid
dehydrogenase [54] is published.
SHAPE-BASED PHARMACOPHORES
Shape of a molecule or an assembly of molecules has
been utilized in the area of QSAR via comparative molecular
field analysis (CoMFA) [55], as well as molecular shape
analysis [56]. Shape based on a group of aligned molecules
was also used to depict a putative receptor active site [57,
58]. Use of shape as pharmacophores for database searching
is relatively recent application. As mentioned earlier, Van
Drie has proposed “shrink-wrap surfaces” to be used as
shape-based 3D database searching [59], and around the same
time frame, Hahn proposed shape queries [60]. Both papers
were published in the same issue of the Journal of Chemical
Information and Computer Sciences. The latter approach
became commercialized within the Catalyst program. Fig (5)
displays how the pharmacophore model that was shown in
Fig (3) can be enhanced using the shape of the molecule.
PREDICTIVE PHARMACOPHORE MODELS
CoMFA is one of the earliest pharmacophore methods
that are used to develop predictive models (mostly referred
to as 3D-QSAR methods) [31]. This technology that has
been commercialized within SYBYL by Tripos, has been
very widely utilized in early computer-aided drug discovery
approaches. As such there is a large number of research
reports that are published, review articles [61], as well as
scope and limitations of the approach [62]. Clark and co-
workers have recently published a good overview and review
of CoMFA [63]. Other applications in this category include
an expert system, Apex-3D [32], and HypoGen [33]. The
latter is a commercially available program from Accelrys and
the predictive models developed with this method can be
used to search databases to retrieve lead compounds. Many
Current Topics in Medicinal Chemistry, 2002, Vol. 2, No. 12 1325
examples of successes with this approach are published (see
later).
PHARMACOPHORE KEYS OR FINGERPRINTS
During the rapid evolution of the experimental
combinatorial chemistry technology in the industry, it
became possible to synthesize large number of compounds
simultaneously [64, 65]. Soon companies were overwhelmed
with the increasing numbers of chemical compounds that are
being created in this process and new computational
methods were developed to manage the influx of this data.
Wendy Warr provided a good overview of the transition of
R&D through combinatorial chemistry and how software
tools were developed to address the needs in the industry
[66]. Combinatorial library design and analysis tools
required some statistical approaches to sample and profile
combinatorial libraries of compounds. Such diversity
assessment tools required effective use of so-called
fingerprints or keys that represent topological aspects of
chemical compounds. These keys and fingerprints were
originally developed for indexing structural databases to
make the searches more effective, and later used for various
similarity assessments. Since these keys were used for
similarity analyses already, it was convenient to start using
them for diversity analyses as well. Earlier papers report the
appropriateness of 2D vs. 3D keys for the use of compound
selection [67] and ligand-receptor binding [68], where
topological keys were deemed more useful.
As the 3D keys were developed further, Jon Mason and
co-workers proposed the concept of using pharmacophore
keys for such diversity analyses [69]. Utilization of the
features used for pharmacophores (such as h-bond donors and
acceptors) as the source of 3D keys, Mason et al. developed
a diversity assessment method, through use of 3-center
pharmacophores present within a molecule as the descriptor.
One limitation of using 3-center pharmacophores was the
inability to recognize chirality. Soon after, Mason and co-
workers developed a 4-center pharmacophore method for
molecular similarity and diversity computations [70].
Pharmacophore fingerprints were also used in QSAR
analyses [71]. Recently, Makara reported a distance-based
method (so called total pharmacophore diversity) and
suggested that 3D pharmacophore methods are superior to
2D binary fingerprints in molecular recognition tests [72].
This paper possibly concluded the scientific controversy that
was started with Brown and Martin [67] on 2D or 3D keys
and which were better for assessing similarity/diversity of
molecules.
PHARMACOPHORE SCORING AND HIT LIST
ANALYSIS
A metric for analyzing hit lists and pharmacophores, so-
called GH-score, was developed and reported by Güner and
Henry [73]:
Ha (3A+Ht) Ht−Ha
GH = × 1−
4Ht A D− A
1326 Current Topics in Medicinal Chemistry, 2002, Vol. 2, No. 12 Osman F. Güner

where, query optimization [77]. Norinder used a similar approach

Ha is the number of active compounds in the hit list
Ht is the total number of the compounds in the hit list
A is the number of active compounds in the database, and
D is the total number of compounds in the database.
for the optimization of predictive pharamacophores. Though
in his case, he used the experimental data and sum of
squares between the calculated and experimental activities
instead of GH-score. In this manner, he optimized the model
to maximize the correlation between experimental activities
and calculated predictions [78].

This method is based on a weighted linear combination PHARMACOPHORES FOR ADME PROFILING
of two competing factors in assessing the quality of the hit
Pharmacophore technology also contributes to the
list: (1) selectivity and (2) coverage. Selectivity is
predictive in silico ADME arena. About 50% of all known
represented by the ratio of active compounds in the hit list
drugs are metabolized in the liver through the subsystems of
to the number of compounds in the hit list (i.e., Ha/Ht), and
cytochrome P-450 (CYP) [119]. Selective inhibition of the
it signifies how selective a pharmacophore is with respect to
subtypes may cause fatal drug-drug interactions. For
retrieving active compounds from a database search.
example Posicor® (Mibefradil), a drug for hypertension, was
Coverage is represented by the ratio of active compounds in
voluntarily withdrawn by Roche due to drug-drug
the hit list to the number of active compounds in the
interactions. It turned out that Posicor reduced the activity of
database (i.e., H a/A), and it signifies the percentage of the
CYP3A4 subsystem and at that time, there were at least two
known active compounds in the database retrieved. It is
optimal to maximize both of these parameters. dozen other drugs that depended on the availability of the
3A4 subsystem (and due to the slowing of the metabolism
Examples of how GH-score is used to analyze the through 3A4 caused these drugs to increase at toxic levels in
different aspects of pharmacophores and database search hit the patients body).
lists are published in the chapter following the GH-score
Sean Ekins proposed a method for identifying potential
paper in the pharmacophore book [74]. Willett and co-
drug-drug interactions using a grid of pharmacophore models
workers used an early version of the GH-score method for
[79]. He proposed pharmacophore models for several
similarity search retrieval effectiveness [75]; following an
important subsystems including 1A2, 2B6, 2C9, 2C19,
analysis of various measures for fragment based 2D
2D6, 2E1, and 3A4 be developed and used for screening
similarity searches, they concluded that cumulative recall
library of compounds, Fig. (6). The output will provide a
and GH-score measures were the most useful of those tested.
matrix of affinities that can then be used to flag out
In a more recent paper, Raymound and Willett utilized GH-
potentially problematic compounds. Ekins, went further in
score as one of the measures for the effectiveness of graph-
his proposal and have actually developed and published
based and fingerprint-based similarity measures for virtual
several of these models: Inhibition pharmacophores for
screening of 2D structures [118]. Other published
CYPs 2C9 [80], 2D6 [81], 3A4 [82], as well as substrate
applications of GH-score include prioritization of virtual
pharmacophores for CYPs 2B6 [83], and 3A4 [84].
high-throughput screening results [76], and database search

where: FMO, flavin containing monooxygenase; NAT, N-acetyltransferase; EH, epoxide hydrolase; GTs, uridininediphosphateglucuronosyltransferases;
STs, sulfotransferases
Fig. (6). A schematic of an in silico parallel screening strategy for drug metabolizing enzyme and transporter pharmacophore models.
Reprinted with permission from [79]. © 2000 IUL.
History and Evolution of the Pharmacophore Concept
PHARMACOPHORES THAT ARE USED IN
FRAGRANCE INDUSTRY – OLFACTOPHORES
A recent review article on the chemistry of odorants by
Philip Kraft and co-workers presents a very detailed picture
on how the SAR concept of drug research are applied in the
fragrances and flavors industry [85]. While this review
extensively covers many aspects of developments in
fragrances, it also provides 3D pharmacophore models
(olfactophores) for various scents, including: fruity pear
odorants, Galbanium (pineapple like), Muguet (scent of lily
flowers), Sandalwood, Amber, and Musk odorants. Some of
these olfactophores were published previously. Kansy and
co-workers published a new olfactophore for musk odor [86],
and challenged earlier reports by Bersuker and co-workers
[87]. Bersuker and co-workers have been promoting 3D
electron topological approach for fragrance prediction and
have published several papers involving: garlic aroma [88],
and meat odor [89]. We are aware of one other sandalwood
olfactophore proposed by Bajgrowicz and Frater [90]. This is
certainly an area of exceptional growth for the use of
pharmacophore technologies.
PHARMACOPHORES FILED FOR PATENTS
Can pharmacophores be patented (we have certainly not
seen QSAR models patented)?. While the jury is still out on
this question, there have been several patent applications
where the primary innovation is a pharmacophore model.
While these patents are not yet issued we may expect to see
more of such applications. The first three applications below
are based on pharmacophore models developed by Catalyst.
WO 98/04913
Filed in 24 July 1997 by Juswinger Singh and co-
workers, this was an application by Biogen for
pharmacophore model for VLA-4 inhibitors. The patent
application was also extended to cover methods of
discovering molecules which may inhibit VLA-4 binding to
its ligands as well as novel molecules which have features
which map to the claimed pharmacophore model.
WO 98/46630
Filed in 16 April 1998 by Terance Hart and co-workers,
this was an application by Peptide Therapeutics Limited for
pharmacophore model for Hepatitis C NS3 Protease
Inhibitors. Pharmacophore model was generated by aligning
peptide substrates inside the active site of the enzyme.
Compounds mapping to the pharmacophore were shown to
be inhibitors of Hepatitis NS3 Protease.
US 2002/0013372
Filed on March 12, 2001 by Sean Ekins, this is an
application by Pfizer Inc. for identification of CYP2D6
inhibitors. The coverage includes screening of selective
serotonin reuptake inhibitors, which do not possess
Current Topics in Medicinal Chemistry, 2002, Vol. 2, No. 12 1327
significant inhibitory potency towards cytochrome P-450
enzymes, in particular, CYP2D6.
US 6,343,257
Filed on April 23, 1999 by Roberto Olender and Rakefet
Rosenfeld, this was an application by Peptor Ltd. That
involves the process of developing a pharmacophore; using
the pharmacophore in screening virtual library of scaffolds;
use of these scaffolds to design new compounds.
LIST OF RECENTLY PUBLISHED (2000-2002)
PHARMACOPHORES
Most of the published successes with pharmacophores
until the year 1999 are covered in a review article by Kurogi
and Güner [4]. In this section, we will summarize more
recent publications. These models include calcium channel
blockers [91], GABA subtypes inhibitors [92], dopamine D4
receptor antagonists [93] and [94], Thymidylate Synthase
inhibitors [95], tyrosine kinase inhibitors [96], bradykinin
B2-receptor antagonists [97], serotonin 5-HT7 antagonists
[98], 5-HT Subtypes inhibitors [99], other serotonin
inhibitors [100], α1 adrenoceptor antagonists [101] and
[102], antitubercular compounds [103], opioid receptor
agonists [104], thermolysin and glycogen phosphorelase
inhibitors [105], N-myristoyltransferase inhibitors [106],
mesangial cell proliferation inhibitors [107], 5α-reductase
inhibitors [108], retinoid X receptor specific ligands [109],
LTD4 receptor antagonists [94], HIV-1 integrase inhibitors
[45], monoaminooxidase B inhibitors [110], thrombin
inhibitors [111], neuronal nicotinic receptor agonists [112],
cyclooxygenase-2 selective Inhibitors [113], dihydrofolate
reductase inhibitors [114], aldose reductase inhibitors and
retinoid acid receptor ligands [115], human pregnane-X
receptor ligands [120], hERG potassium channel inhibition
[121], p-glycoprotein inhibitors [122] and substrates [123],
Antifungal N-Myristoyltransferase Inhibitors [124],
Urotensin II Receptor Antagonists [125], as well as viral
inhibitors such as rhinovirus replication inhibitors [116] and
parainfluenza 1 virus inhibitors [117].
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