Current
Computer-Aided Drug Design
ISSN: 1573-4099
Current Computer-Aided
Drug Design
Volume 4, Number 3, September 2008
Contents
Editorial Pp. 154-155
Collections of Compounds – How to Deal with them?
Pp. 156-168
Julie Dubois, Stéphane Bourg, Christel
Vrain and Luc Morin-Allory
[Abstract]
Calculating the Protonation States of
Proteins and Small Molecules: Implications to Ligand-Receptor
Interactions Pp. 169-179
Rooplekha Mitra, Radhey Shyam, Indranil
Mitra, Maria A. Miteva and Emil Alexov
[Abstract]
Ligand-Based Approaches in Virtual Screening
Pp. 180-190
Dominique Douguet
[Abstract]
ISIDA - Platform for Virtual Screening
Based on Fragment and Pharmacophoric Descriptors Pp.
191-198
Alexandre Varnek, Denis Fourches, Dragos Horvath, Olga
Klimchuk, Cedric Gaudin, Philippe Vayer, Vitaly Solov’ev,
Frank Hoonakker, Igor V. Tetko and Gilles Marcou
[Abstract]
Pharmacophores of 5-HT4
Receptor Ligands: Experience of CERMN and Implications for
Drug Design Pp. 199-208
Ronan Bureau, Thibault Varin, Alban Lepailleur, Cyril Daveu,
Stephane Lemaître, Jean-Charles Lancelot, Aurelien Lesnard,
Sabrina Butt Gueulle, François Dauphin and Sylvain
Rault
[Abstract]
How to Measure the Similarity Between Protein Ligand-Binding
Sites? Pp. 209-220
Esther Kellenberger, Claire Schalon and
Didier Rognan
[Abstract]
Docking and High Throughput Docking:
Successes and the Challenge of Protein Flexibility Pp.
221-234
Claudio N. Cavasotto and Narender Singh
[Abstract]
Docking and Biomolecular Simulations
on Computer Grids: Status and Trends Pp.
235-249
Alexandru-Adrian Tantar, Sébastien
Conilleau, Benjamin Parent, Nouredine Melab, Lorraine Brillet,
Sylvaine Roy, El-Ghazali Talbi and Dragos Horvath
[Abstract]
Combining Ligand- and Structure-Based
Methods in Drug Design Projects Pp. 250-258
Olivier Sperandio, Maria A. Miteva and
Bruno O. Villoutreix
[Abstract]
Abstracts
[Back to top]
Editorial:
Virtual screening (VS) is now widely applied as a hit-finding
(or a hit-to-lead) methodology within drug discovery and chemical
biology campaigns. The term virtual screening has to be considered
as an umbrella term for a variety of ligand- and structure-based
tools, and, through database mining, one notices that VS keyword
refers to both, methodological developments and/or applications
of these in silico methods to selected targets. The growth
of publications with virtual-ligand-screening term as keywords
is noticeable with 11 articles found at PubMed between January
2000 to January 2001 and 148 articles from January 2007 to
January 2008. Clearly, the figure will rise in the coming
years. This special issue describes the current state of the
art and progress made in the field and presents: methods to
prepare/analyse compound collections and targets, ligand-based
and structure-based approaches and successful examples of
applications. Current challenges are also discussed. It is
concluded that virtual screening methods are continuously
evolving and have contributed to the discovery of several
compounds that have entered or will enter clinical trials.
Here again, I would like to thank the authors for preparing
these manuscripts and Dr. Sperandio and Dr. Miteva for helping
me assembling this special issue.
Prior to starting a VS project, one needs to prepare the compound
collection(s) and the targets. Many chemical libraries are
available to users, there are many computer programs to prepare,
manipulate and maintain them, but in practice, how to deal
with these collections, which filters to apply, which descriptors
play a critical role, how diversity and similarity could be
assessed ? Different opinions and strategies to prepare compound
collections are reviewed in the manuscript: “Collections
of Compounds – How to Deal with them?”
by J. Dubois, S. Bourg, C. Vrain and L. Morin-Allory.
With regard to target preparation, several key aspects have
to be considered, ranging from protonation states to flexibility
of the receptor. Yet, if we focus here for a moment on prediction
of protonation states we note that this also applies to small
chemical compounds. Biological ligand-receptor interactions
occur in specific environments in the body, at a specific
pH and ion concentration. Certainly, compound collections
and targets should be investigated and prepared accordingly.
It is however very challenging to predict the ionization state
of titratable groups as it depends on numerous factors. At
least, the ionization states could be predicted prior to application
of in silico screening protocols. Differences in the size
of the receptors and the ligands, and the number of computations
required to treat a large compound collection, imply different
computational approaches in predicting pKa’s of ionizable
groups for the receptor and for the chemical compounds. The
current state-of-the-art in developing methods for predicting
the protonation states of both, the receptor and the chemical
compounds are reviewed in the manuscript “Calculating
the Protonation States of Proteins and Small Molecules: Implications
to LIGAND-Receptor Interactions” by R. Mitra,
R. Shyam, I. Mitra, M. A. Miteva and E. Alexov.
Once the compound collections are prepared, it is then possible
to start VS computations. There are two main strategies, “ligand-based”
screening and “structure-based” screening. There
are numerous ligand-based methods, and the computational strategy
that one needs to apply varies from case to case and depends
on the goals: lead hunting or lead optimization, requirement
for a novel lead class, type of biological assay, structural
information available, known classes of ligands, allocated
chemistry resources. In the article “Ligand-Based
Approaches in Virtual Screening”, D. Douguet
describes the various strategies commonly used and underlines
the current trends and future directions of ligand-based screening.
New tools to perform similarity searches and assess some ADME/Tox
properties are needed. A new software named ISIDA is presented
in the context of existing tools and knowledge. The manuscript
“ISIDA - Platform for Virtual Screening Based
on Fragment and Pharmacophoric Descriptors”
by A. Varnek, D. Fourches, D. Horvath, O. Klimchuk, C. Gaudin,
P. Vayer, V. Solov’ev, F. Hoonakker, I. V. Tetko, G.
Marcou explains the descriptors and workflows used in that
package. Several examples of applications are discussed with
a particular attention to mining reaction databases.
Applications of “ligand-based” methods are provided
in the manuscript “Pharmacophores of 5-HT4 Receptor
Ligands: Experience of CERMN and Implications for Drug Design”
by R. Bureau, T. Varin, A. Lepailleur, C. Daveu, S. Lemaître,
J-C. Lancelot, A. Lesnard, S. Butt, F. Dauphin, S. Rault.
In that study, the authors explain how to define pharmacophores
for 5-HT4 receptor agonists
and antagonists and highlight the importance of this step
for the design of new selective ligands for this receptor.
The different in silico-in vitro studies give interesting
insights into the structural modifications that appear to
be of pivotal importance for the activity of 5-HT4
receptor ligands.
When the 3D structure of the receptor is available, then structure-based
approaches can be applied. In many situations, it could be
valuable to be able to compare binding pockets. Indeed, quantification
of local similarity between protein 3D structures is a promising
tool in the computer-aided drug design field. Over the last
ten years, several computational methods were proposed, mostly
based on geometrical comparisons. The manuscript “How
to Measure the Similarity Between Protein Ligand-Binding Sites?”
by E. Kellenberger, C. Schalon and D. Rognan summarizes the
recent literature on this topic and gives an overview of available
programs. The article points out strengths and weaknesses
of the various approaches and several examples are presented
to illustrate the wide applicability domain of some methods,
from detection of common structural motifs, identification
of secondary targets for a drug-like compound, comparison
of binding sites across a functional family, comparison of
homology models to database screening.
In spite of its many successes, structure-based virtual screening
still has several limitations. One major problem is receptor
flexibility. In the manuscript “Docking and
High Throughput Docking: Successes and the Challenge of Protein
Flexibility”, C. N. Cavasotto and N. Singh
first present the latest successful stories in high-throughput
docking. After reviewing the concepts of protein dynamics
and binding, and its impact in ligand docking, the current
approaches to incorporate protein mobility in docking-based
virtual screening are presented and discussed.
Docking-scoring methods are very computer intensive approaches.
Strategies and protocols have to be divided to be able to
deal with such heavy computations. The manuscript “Docking
and Biomolecular Simulations on Computer Grids: Status and
Trends” by A.-A. Tantar, S. Conilleau, B. Parent,
N. Melab, L. Brillet, S. Roy, El-G. Talbi and D. Horvath outlines
the recent developments in the field of large-scale parallel
computing applied to molecular simulations. The paper is intended
to be an introductive material aiming at narrowing the “cultural
gap” between the developers and users of molecular simulations
(chemists, medicinal chemists and biologists – typical
workstation users) and the informatics experts in massively
parallel computation. The article starts with a brief overview
of the existing molecular simulation techniques. Docking procedures
are the most discussed, given the high importance of this
application in computer-aided drug design. An introduction
to computer grids is logically pursued with the presentation
of some of the most promising large-scale parallel molecular
simulations already performed. Then, the authors’ own
research program, Docking@Grid, is briefly discussed.
As we have all observed, in today’s drug discovery projects,
the use of virtual screening tools, either ligand-based or
structure-based techniques, is gaining momentum. Yet, some
inherent limits are associated with each of these screening
techniques that are not about to be easily solved. As such,
their combination in so-called hybrid protocols can help to
balance these limitations and capitalize on their mutual strengths.
In the article “Combining Ligand- and Structure-Based
Methods in Drug Design Projects”, O. Sperandio,
M.A. Miteva and B.O. Villoutreix review some recent studies
integrating ligand- and structure-based screening protocols.
Bruno O. Villoutreix
INSERM U648 (MTi)
Universite Paris-7 Diderot
5 rue Marie Andree Lagroua Weill-Halle
75013 Paris
France
E-mail: bruno.villoutreix@univ-paris-diderot.fr
[Back to top]
Collections of Compounds – How to Deal with
them?
Julie Dubois, Stéphane Bourg, Christel
Vrain and Luc Morin-Allory
Chemical libraries or databases are collections of compounds
which can be screened (virtually or experimentally) in order
to discover drug candidates. These libraries are very variable
in their content (description of structures, molecular descriptors,
literature links...) and their size (number of compounds).
Over the last decade, a large number of papers have been published
on the subject. In this review, we summarize these studies
by introducing different types of compound collections and
reviewing the main kinds of software used to manipulate them.
We present the descriptors which have a fundamental role in
the characterisation of the molecules, and describe how they
are used to define the molecular filters applied before screening,
in order to obtain both a representation of chemical spaces
and selections of subsets by diversity or similarity.
[Back to top]
Calculating the Protonation States of Proteins and Small Molecules:
Implications to Ligand-Receptor Interactions
Rooplekha Mitra, Radhey Shyam, Indranil
Mitra, Maria A. Miteva and Emil Alexov
Ionized groups carry net charge and thus play a major
role in the electrostatic interactions between the ligand
and receptor. However, their ionization states depend on such
factors as the pH of the water phase, the interactions with
other charges and with water molecules. Therefore, the ionization
states must be predicted prior to the application of in
silico screening or docking protocols. A typical virtual
screening protocol searches for new heat compounds by testing
hundreds of thousands or millions of small molecules against
a particular target receptor. Differences in the size of receptors
and the ligand, and the large number of small molecules to
screen, require different computational approaches in predicting
pKa’s of ionizable groups. On the receptor side, while
the computational protocol does not have to be fast, it must
account for shape of the receptor and the long range interactions
of all ionizable groups within. Conversely, while the calculations
of the ionization states of the ligand must be fast, they
do not have to consider many long range interactions because
of the small size of the ligand. These requirements resulted
in the development of different protocols for computing pKa’s
of the receptor and the ligand. The advantages and disadvantages
of both are outlined in this paper. In addition, the formation
of the receptor-ligand complex could dramatically change the
electrostatic environment of the ionizable groups and cause
proton uptake/release. Accounting for such phenomena can be
critical for obtaining correct docking solutions.
[Back to top]
Ligand-Based Approaches in Virtual Screening
Dominique Douguet
Although there are many more receptor structures than there
were in the 1970s and 1980s, drug discovery remains dominated
by empirical screening and substrate-based drug design. Computer-aided
drug design methods have become value-adding disciplines that
now contribute to the early stage of the drug discovery process
[1, 2]. Computational methods encompass all aspects of drug
discovery from target assessment to lead optimization. The
computational strategy varies from case to case and can be
influenced by several situational variables: lead hunting
or lead optimization, requirement for a novel lead class,
type of biological assay, structural information available,
known classes of ligands, allocated chemistry resources…
Today, drug discovery is still a complex and approximate science.
Thus, incorporating knowledge-based approaches like ligand-based
screenings may bias the process towards success. This review
describes these strategies with practical applications and
presents future perspectives of ligand-based screening.
[Back to top]
ISIDA - Platform for Virtual Screening Based on Fragment and
Pharmacophoric Descriptors
Alexandre Varnek, Denis Fourches, Dragos
Horvath, Olga Klimchuk,
Cedric Gaudin, Philippe Vayer, Vitaly Solov’ev, Frank
Hoonakker, Igor V. Tetko and Gilles Marcou
In this paper we illustrate the application of the ISIDA
(In SIlico design
and Data Analysis) software
to perform virtual screening of large databases of compounds
and reactions and to assess some ADME/Tox properties. ISIDA
represents an ensemble of tools allowing users to store, search
and analyze the data, to perform similarity searches in large
databases of molecules and reactions, to build and validate
QSAR models, and to generate and screen virtual combinatorial
libraries. It uses its own descriptors (substructural molecular
fragments and fuzzy pharmacophore triplets). Workflow can
be easily organized by combining different ISIDA modules.
Several examples of ISIDA applications (similarity search
of potent benzodiazepine ligands with FPT, QSAR modeling of
aqueous solubility, aquatic toxicity, tissue-air partition
coefficients, anti-HIV activity, and screening of the “Chimiothèque
Nationale” Database), are discussed. Particular attention
is paid to mining reaction databases using Condensed Reaction
Graphs approach.
[Back to top]
Pharmacophores of 5-HT4 Receptor
Ligands: Experience of CERMN and Implications for Drug Design
Ronan Bureau, Thibault Varin, Alban Lepailleur,
Cyril Daveu, Stephane Lemaître, Jean-Charles Lancelot,
Aurelien Lesnard, Sabrina Butt-Gueulle, François Dauphin
and Sylvain Rault
The definitions of pharmacophores for 5-HT4
receptor agonists and antagonists are described in this review.
These pharmacophores were keys in the design of new selective
ligands for this receptor, starting generally from 5-HT3
receptor ligands. Our laboratory has defined two series of
5-HT4 receptor ligands through
comparative analysis of pharmacophores associated with partial
agonists at 5-HT3 receptors
and antagonists at 5-HT4
receptors. For 5-HT4 receptor
agonists, a new 3D-QSAR analysis was carried out leading to
a pharmacophore which we compared to previous data. One of
the main challenges for the study of 5-HT4
receptors is to obtain a clear definition of the pharmacological
profile associated with the ligand derivatives. This is discussed
in terms of the conformational space associated with the receptor
as well as data from site-directed mutagenesis studies. Finally,
all these results allow a more precise description of the
pharmacophores and give interesting insights into the structural
modifications that appear to be of pivotal importance for
the activity of 5-HT4 receptor
ligands.
[Back to top]
How to Measure the Similarity Between Protein Ligand-Binding
Sites?
Esther Kellenberger, Claire Schalon and
Didier Rognan
Quantification of local similarity between protein 3D
structures is a promising tool in computer-aided drug design
and prediction of biological function. Over the last ten years,
several computational methods were proposed, mostly based
on geometrical comparisons. This review summarizes the recent
literature and gives an overview of available programs.
A particular interest is given to the underlying methodologies.
Our analysis points out strengths and weaknesses of the various
approaches. If all described methods work relatively well
when two binding sites obviously resemble each other, scoring
potential solutions remains a difficult issue, especially
if the similarity is low. The other challenging question is
the protein flexibility, which is indeed difficult to evaluate
from a static representation. Last, most of recently developed
techniques are fast and can be applied to large amounts of
data.
Examples were carefully chosen to illustrate the wide applicability
domain of the most popular methods: detection of common structural
motifs, identification of secondary targets for a drug-like
compound, comparison of binding sites across a functional
family, comparison of homology models, database screening.
[Back to top]
Docking and High Throughput Docking: Successes and the Challenge
of Protein Flexibility
Claudio N. Cavasotto and Narender Singh
Protein structure-based approaches in lead optimization
and in silico screening of chemical libraries based
on ligand docking have increasingly become part of many drug
discovery projects, mainly due to the technical improvements
in crystallography, the support of modern software, and the
ever increasing computational power. The use of three-dimensional
structural information of therapeutic targets has long been
recognized to initiate and accelerate many drug design programs
in the past, since it offers the possibility of finding novel
scaffolds, different from the existing active compounds. In
spite of its many successes, structure-based virtual screening
or high throughput docking still has several limitations at
the methodological level, not the least of which is protein
flexibility, ignored by most of the docking programs, which
treat the receptor as a rigid entity. This may impact the
accuracy of virtual screening at the docking and at the scoring
level. The authors will first present the latest successful
stories in high throughput docking. After reviewing the concepts
of protein dynamics and binding, and its impact in ligand
docking, the current approaches to incorporate protein mobility
in docking-based virtual screening will be presented and discussed.
[Back to top]
Docking and Biomolecular Simulations on Computer Grids: Status
and Trends
Alexandru-Adrian Tantar, Sébastien
Conilleau, Benjamin Parent, Nouredine Melab, Lorraine Brillet,
Sylvaine Roy, El-Ghazali Talbi and Dragos Horvath
This article outlines the recent developments in the field
of large-scale parallel computing applied to molecular simulations,
also including some original, preliminary contributions of
the authors. It is not meant to be an exhaustive review paper,
but rather an introductive material aimed at narrowing the
“cultural gap” between the developers and users
of molecular simulations (chemists, medicinal chemists and
biologists – typical workstation users) and the informatics
experts in massively parallel computing. The article starts
with a brief overview of the existing molecular simulation
techniques, in emphasizing the weaknesses of present approaches
and the need for more computer-intensive methods. Docking
procedures are the most discussed, given the high importance
of this application in computer-aided drug design. An introduction
to computer grids is logically pursued with the presentation
of some of the most promising large-scale parallel molecular
simulations already performed. Eventually, the author’s
own research program, Docking@Grid, is briefly discussed.
[Back to top]
Combining Ligand- and Structure-Based Methods in Drug Design
Projects
Olivier Sperandio, Maria A. Miteva and
Bruno O. Villoutreix
In today’s drug discovery projects, the use of
virtual screening tools, either ligand-based or structure-based
techniques, is gaining momentum. Taken separately, these techniques
obviously present some genuine advantages on some specific
tasks, for example and for a given target, it is possible
to explore the local variation of the chemical space in terms
of structure activity relationship (SAR), or to sample the
pharmaco-topological profile of potential hit molecules in
a target structure driven manner (docking). Thus, while inherent
limits are associated with each of these screening techniques
that are not about to be easily solved, their combination
in a hybrid protocol can help to balance these limitations
and capitalize on their mutual strengths. Here we review some
recent studies integrating ligand- and structure-based screening
protocols, and show how this concept directly benefits the
quality of the hit molecules.
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