Combinatorial
Chemistry & High Throughput Screening
ISSN: 1386-2073
Combinatorial Chemistry &
High Throughput Screening
Volume 11, Number 8, September 2008
Contents
Chemogenomics
Guest Editor: Eric Maréchal
Editorial Pp. 582
Chemogenomics: A Discipline at the Crossroad of High
Throughput Technologies, Biomarker Research, Combinatorial
Chemistry, Genomics, Cheminformatics, Bioinformatics and Artificial
Intelligence Pp. 583-586
Eric Maréchal
[Abstract]
Expanding the Chemical Space in Practice: Diversity-Oriented
Synthesis Pp. 587-601
Marine Peuchmaur and Yung-Sing Wong
[Abstract]
Cell-Based Assays in Practice: Cell Markers
from Autofluorescent Proteins of the GFP-Family Pp.
602-609
Michael Wolff, Simone Kredel, Jörg
Wiedenmann, G. Ulrich Nienhaus and Ralf Heilker
[Abstract]
Design of Phenotypic Screens for Bioactive
Chemicals and Identification of their Targets by Genetic and
Proteomic Approaches Pp. 610-616
David C. Schriemer, Danielle Kemmer and
Michel Roberge
[Abstract]
Chemogenomics and Cancer Chemotherapy:
Cell-Based Assays to Screen for Small Molecules that Impair
Microtubule Dynamics Pp. 617-623
Laurence Lafanechère
[Abstract]
Chemogenomics and Parasitology: Small
Molecules and Cell-Based Assays to Study Infectious Processes
Pp. 624-646
Marc A.T. Muskavitch, Natasha Barteneva
and Marc-Jan Gubbels
[Abstract]
Plant Pathogen Recognition as a Natural,
Original and Simple Model for Chemogenomics: A Brief Overview
of Cell-Based Assays to Screen for Peptides Acting as Plant
Defense Activators Pp. 647-652
Masahiro Miyashita and Hisashi
Miyagawa
[Abstract]
Building a Biological Space Based on
Protein Sequence Similarities and Biological Ontologies
Pp. 653-660
Paul Kersey, David Lonsdale, Nicky J. Mulder,
Robert Petryszak and Rolf Apweiler
[Abstract]
Building a Chemical Space Based on Fragment
Descriptors Pp. 661-668
Igor Baskin and Alexandre Varnek
[Abstract]
A Ligand-Based Approach to Mining the
Chemogenomic Space of Drugs Pp. 669-676
Elisabet Gregori-Puigjané and
Jordi Mestres
[Abstract]
Machine Learning for In Silico
Virtual Screening and Chemical Genomics: New Strategies
Pp. 677-685
Jean-Philippe Vert and Laurent
Jacob
[Abstract]
Meet
the Guest Editor Pp. 686
Abstracts
[Back to top]
Editorial: Chemogenomics: A Discipline at the Crossroad
of High Throughput Technologies, Biomarker Research, Combinatorial
Chemistry, Genomics, Cheminformatics, Bioinformatics and Artificial
Intelligence
Chemogenomics is a recent scientific discipline that
can be defined as the study of the interaction of functional
biological systems with exogenous small molecules, or in broader
sense the study of the intersection of biological and chemical
spaces. This ambitious objective requires expertise in biology,
chemistry and computational sciences (bioinformatics, cheminformatics,
large scale statistics and machine learning methods) but it
is more than a simple apposition of each of these disciplines.
Working together, biologists, chemists, and computer scientists
have to find their common language and shared concepts.
Biological entities interacting with small molecules can be
isolated proteins or more elaborate systems, from single cells
to complete organisms. The biological space is therefore analyzed
at various genomic levels (genomic, transcriptomic, proteomic
or any phenotypic level). The space of small molecules is
partially real, corresponding to commercial and academic collections
of compounds, and partially virtual, corresponding to the
chemical space possibly synthesizable. Synthetic chemistry
has developed novel strategies allowing a physical exploration
of this universe of possibilities. A major challenge of cheminformatics
is to charter the virtual space of small molecules using realistic
biological constraints (bioavailability, druggability, structural
biological information). Chemogenomics is a descendent of
conventional pharmaceutical approaches, since it involves
the screening of chemolibraries for their effect on biological
targets, and benefits from the advances in the corresponding
enabling technologies and the introduction of new biological
markers. Screening was originally motivated by the rigorous
discovery of new drugs, neglecting and throwing away any molecule
that would fail to meet the standards required for a therapeutic
treatment. It is now the basis for the discovery of small
molecules that might or might not be directly used as drugs,
but which have an immense potential for basic research, as
probes to explore an increasing number of biological phenomena.
Concerns about the environmental impact of chemical industry
also open new fields of research for chemogenomics.
In this special issue (CCHTS Vol. 11, No.
8), biologists, chemists, computer scientists and
mathematicians help to capture a global view, shedding light
on the diverse aspects of chemogenomics. Together, their focused
reviews illustrate how this discipline is at the crossroad
of high throughput technologies, biomarker research, combinatorial
chemistry, genomics, cheminformatics, bioinformatics and artificial
intelligence.
Eric Maréchal
Unité Mixte de Recherche 5168 CNRS-CEA-INRA-Université
Joseph Fourier
Institut de Recherches en Technologies et Sciences pour le
Vivant
17 avenue des Martyrs
38058 Grenoble
France
E-mail: eric.marechal@cea.fr
[Back to top]
Chemogenomics: A Discipline at the Crossroad of High Throughput
Technologies, Biomarker Research, Combinatorial Chemistry,
Genomics, Cheminformatics, Bioinformatics and Artificial Intelligence
Eric Maréchal
Chemogenomics is the study of the interaction of functional
biological systems with exogenous small molecules, or in broader
sense the study of the intersection of biological and chemical
spaces. Chemogenomics requires expertises in biology, chemistry
and computational sciences (bioinformatics, cheminformatics,
large scale statistics and machine learning methods) but it
is more than the simple apposition of each of these disciplines.
Biological entities interacting with small molecules can be
isolated proteins or more elaborate systems, from single cells
to complete organisms. The biological space is therefore analyzed
at various postgenomic levels (genomic, transcriptomic, proteomic
or any pheno-typic level). The space of small molecules is
partially real, corresponding to commercial and academic collections
of compounds, and partially virtual, corresponding to the
chemical space possibly synthesizable. Synthetic chemistry
has developed novel strategies allowing a physical exploration
of this universe of possibilities. A major challenge of chemin-formatics
is to charter the virtual space of small molecules using realistic
biological constraints (bioavailability, druggability, structural
biological information). Chemogenomics is a descendent of
conventional pharmaceutical approaches, since it involves
the screening of chemolibraries for their effect on biological
targets, and benefits from the advances in the corresponding
enabling technologies and the introduction of new biological
markers. Screening was originally motivated by the rigorous
discovery of new drugs, neglecting and throwing away any molecule
that would fail to meet the standards required for a therapeutic
treatment. It is now the basis for the discovery of small
molecules that might or might not be directly used as drugs,
but which have an immense potential for basic research, as
probes to explore an increasing number of biological phenomena.
Concerns about the environmental impact of chemical industry
open new fields of research for chemogenomics.
[Back to top]
Expanding the Chemical Space in Practice: Diversity-Oriented
Synthesis
Marine Peuchmaur and Yung-Sing Wong
Diversity-Oriented Synthesis (DOS) aims to broaden the
frontier of accessible collections of complex and diverse
small molecules. This review endeavours to dissect the DOS
concept through three elements of diversity: building block,
stereochemistry, and skeleton. Recent examples in the literature
that emphasize the efficient combinations of these elements
to generate diversity are reported.
[Back to top]
Cell-Based Assays in Practice: Cell Markers from Autofluorescent
Proteins of the GFP-Family
Michael Wolff, Simone Kredel, Jörg
Wiedenmann, G. Ulrich Nienhaus and Ralf Heilker
The more recently discovered anthozoan fluorescent proteins
(FPs) and the classic Aequorea victoria Green Fluorescent
Protein (avGFP) as well as their derivatives have become versatile
tools as live cell markers in fluorescence microscopy. In
this review, we show the use of these FPs in drug discovery
assays. Assay examples are given for the application of FPs
in multiplexed imaging, as photosensitizers, as fluorescent
timers, as pulse-chase labels and for robotically integrated
compound testing. The development of fast microscopic imaging
devices has enabled the application of automated fluorescence
microscopy combined with image analysis to pharmaceutical
high throughput drug discovery assays, generally referred
to as High Content Screening (HCS).
[Back to top]
Design of Phenotypic Screens for Bioactive Chemicals and Identification
of their Targets by Genetic and Proteomic Approaches
David C. Schriemer, Danielle Kemmer and
Michel Roberge
Cell-based screening using phenotypic assays is a useful means
of identifying bioactive chemicals for use as tools to elucidate
complex cellular processes. However, the chemicals must display
sufficient selectivity and their targets have to be identified.
We describe how cell-based screening assays can be designed
to maximize the likelihood of discovering selective compounds
through the choice of positive readouts, low chemical concentrations
and long incubation periods. Examining the potency, efficacy
and activity range of chemicals can further help set apart
those likely to act more specifically. Identifying the cellular
targets of active chemicals can be especially demanding. Secondary
screens and the cautious use of the candidate approach can
help narrow down their mechanisms of action, but biased approaches
may lead to the identification of secondary or even irrelevant
targets. We discuss strategies for unbiased target identification
by sampling potential targets at the genome-wide and proteome-wide
levels.
[Back to top]
Chemogenomics and Cancer Chemotherapy: Cell-Based Assays to
Screen for Small Molecules that Impair Microtubule Dynamics
Laurence Lafanechère
Microtubules are still a promising target for new
therapeutic agents. Thus, there is a continuous interest for
compounds able to modify microtubule assembly, either by interacting
directly with tubulin, or by interacting with microtubules
regulators. Because of its dynamic characteristics, the microtubule
cytoskeleton is a suitable target for small molecules that
rapidly diffuse in the cell cytoplasm. Moreover, compounds
targeting the microtubule cytoskeleton have proved to be valuable
tools for basic research in cell biology. In this paper, after
a short presentation of the apparent molecular pathways involved
in the anticancer effect of agents that interfere with microtubules
functions, the potentials and impact of chemogenomics and
cell-based assays in the discovery of new therapeutic compounds
and of new regulators of the microtubule cytoskeleton are
described.
[Back to top]
Chemogenomics and Parasitology: Small Molecules and Cell-Based
Assays to Study Infectious Processes
Marc A.T. Muskavitch, Natasha Barteneva
and Marc-Jan Gubbels
Infectious diseases caused by protozoan parasites - malaria,
sleeping sickness, leishmaniasis, Chagas’ disease, toxoplasmosis
- remain chronic problems for humanity. We lack vaccines and
have limited drug options effective against protozoa. Research
into anti-protozoan drugs has accelerated with improved in
vitro cultivation methods, enhanced genetic accessibility,
completed genome sequences for key protozoa, and increased
prominence of protozoan diseases on the agendas of well-resourced
public figures and foundations. Concurrent advances in high-throughput
screening (HTS) technologies and availability of diverse small
molecule libraries offer the promise of accelerated discovery
of new drug targets and new drugs that will reduce disease
burdens imposed on humanity by parasitic protozoa. We provide
a status report on HTS technologies in hand and cell-based
assays under development for biological investigations and
drug discovery di-rected toward the three best-characterized
parasitic protozoa: Trypanosoma brucei, Plasmodium falciparum,
and Toxoplasma gondii. We emphasize cell growth assays
and new insights into parasite cell biology speeding development
of better cell-based assays, useful in primary screens for
anti-protozoan drug leads and secondary screens to decipher
mechanisms of action of leads identified in growth assays.
Small molecules that interfere with specific aspects of protozoan
biology, identified in such screens, will be valuable tools
for dissecting parasite cell biology and developing anti-protozoan
drugs. We discuss potential impacts on drug development of
new consortia among academic, corporate, and public partners
committed to discovery of new, effective anti-protozoan drugs.
[Back to top]
Plant Pathogen Recognition as a Natural, Original and Simple
Model for Chemogenomics: A Brief Overview of Cell-Based Assays
to Screen for Peptides Acting as Plant Defense Activators
Masahiro Miyashita and Hisashi
Miyagawa
As plants lack a circulatory system and adaptive immune system,
they have evolved their own defense systems distinct from
animals, in which each plant cell is capable of defending
itself from pathogens. Plants induce a number of defense responses,
which are triggered by a variety of molecules derived from
pathogenic microorganisms, referred to as microbe-associated
molecular patterns (MAMPs), including peptides, proteins,
lipopolysaccharide, β-glucan,
chitin, and ergosterol. The interaction between plants and
chemicals in the context of plant defense represents a “natural”
and simple model for chemogenomics, at the intersection between
chemical and biological diversities. For protection of crop
plants from diseases, it has been shown to be effective to
stimulate the plant immunity by chemical compounds, the so-called
“plant defense activators”. Combinatorial chemistry
techniques can be applied to the search for novel plant defense
activators, but it is essential to establish an efficient
and reliable screening system suitable for library screening.
For studies of the plant immune system, it is difficult to
use isolated proteins as biological targets because the receptors
for MAMP recognition are largely unknown and even the receptors
identified so far are transmembrane proteins. Therefore, screening
for novel peptides acting on MAMP receptors from combinatorial
libraries must rely on a solution-phase assay using cells
as the biological targets. In this review, we introduce the
cell-based lawn format assay for identification of peptides
acting as plant defense activators from combinatorial peptide
libraries. The requirements and limitations in constructing
the screening system using combinatorial libraries in the
studies of plant sciences are also discussed.
[Back to top]
Building a Biological Space Based on Protein Sequence Similarities
and Biological Ontologies
Paul Kersey, David Lonsdale, Nicky J. Mulder,
Robert Petryszak and Rolf Apweiler
Assignment of function to protein sequence is a task of growing
importance in the life sciences, as new high-throughput sequencing
DNA technologies generate ever increasing quantities of genomic
and meta-genomic data. Patterns within the sequence space,
caused by the evolutionary conservation and assembly of protein
domains, make possible the inference of function from sequence
similarity. Clustering similar sequences is a useful technique
for finding conserved sequences; the CluSTr database is a
publicly-available database arranging proteins in a hierarchy
structured by similarity. The protein classification tool
InterProScan builds on this approach by applying a range of
methods to detect proteins that contain signatures indicative
of the presence of particular conserved domains. The use of
ontologies to describe protein function provides a flexible
and abstract language to classify proteins. Together, these
techniques can provide an understanding of the shape of the
protein space, and can be used to explore the unchartered
waters of the emerging metagenomic world.
[Back to top]
Building a Chemical Space Based on Fragment Descriptors
Igor Baskin and Alexandre Varnek
This article reviews the application of fragment descriptors
at different stages of virtual screening: filtering, similarity
search, and direct activity assessment using QSAR/QSPR models.
Several case studies are considered. It is demonstrated that
the power of fragment descriptors stems from their universality,
very high computational efficiency, simplicity of interpretation
and versatility.
[Back to top]
A Ligand-Based Approach to Mining the Chemogenomic Space of
Drugs
Elisabet Gregori-Puigjané and
Jordi Mestres
The practical implementation and validation of a ligand-based
approach to mining the chemogenomic space of drugs is presented
and applied to the in silico target profiling of
767 drugs against 684 targets of therapeutic relevance. The
results reveal that drugs targeting aminergic G protein-coupled
receptors (GPCRs) show the most promiscuous pharmacological
profiles. The detection of cross-pharmacologies between aminergic
GPCRs and the opioid, sigma, NMDA, and 5-HT3 receptors aggravate
the potential promiscuity of those drugs, predominantly including
analgesics, antidepressants, and antipsychotics.
[Back to top]
Machine Learning for In Silico Virtual Screening
and Chemical Genomics: New Strategies
Jean-Philippe Vert and Laurent
Jacob
Support vector machines and kernel methods belong to
the same class of machine learning algorithms that has recently
become prominent in both computational biology and chemistry,
although both fields have largely ignored each other. These
methods are based on a sound mathematical and computationally
efficient framework that implicitly embeds the data of interest,
respectively proteins and small molecules, in high-dimensional
feature spaces where various classification or regression
tasks can be performed with linear algorithms. In this review,
we present the main ideas underlying these approaches, survey
how both the “biological” and the “chemical”
spaces have been separately constructed using the same mathematical
framework and tricks, and suggest different avenues to unify
both spaces for the purpose of in silico chemogenomics.
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