Current Medicinal Chemistry, Volume 9, No. 23, 2002
Contents
Combinatorial
Chemistry:
Successful
Application to Drug Discovery
Guest
Editors: Matthias Nettekoven / Andrew
W. Thomas
Chemogenomics: Bridging a Drug Discovery Gap Pp.2077-2084
Konrad H. Bleicher
The Application of Multi-Component Reactions
in Drug Discovery
Pp.2085-2093
Lutz
Weber
Trends in Virtual Combinatorial Library
Design Pp.2095-2101
Gisbert Schneider
Analytical Techniques for Small Molecule
Solid Phase Synthesis
Pp.2103-2127
Jan
J. Scicinski, Miles S. Congreve, Corinne Kay and
Steven V. Ley
Natural Product Guided Compound Library
Development Pp.2129-2145
Rolf Breinbauer, Michael Manger, Michael Scheck and Herbert Waldmann
Polymer-Supported Metal-Phosphine
Complexes for use as Catalysts or Linkers in Medicinally-Oriented Organic
Synthesis Pp.2147-2171
Nicholas E. Leadbeater
The Combinatorial Centre of Excellence - A
Unique Industrial & Academic Partnership Pp.2173-2177
Mark Bradley
Accelerating Drug Discovery by Integrative
Implementation of Laboratory Automation in the Work Flow Pp.2179-2190
Matthias
Nettekoven and Andrew W. Thomas
[Back to top] Chemogenomics: Bridging a Drug Discovery Gap
Konrad H. Bleicher
With the successful completion of
the human genome sequencing and the resulting plethora of genetic information
now available novel technologies and applications have to be established to
translate the huge amount of data generated into successful biological and
biomedical research programs. The integration of various drug discovery
disciplines within the parallel quest for novel targets and new molecular
entities has meanwhile given rise to a quite popular term in pharmaceutical
research named “chemogenomics”. This
review article gives an overview of the disciplines involved in this field and
discusses the possible implications of this novel paradigm in drug discovery
for the near future.
[Back to top] The Application of Multi-Component Reactions
in Drug Discovery
Lutz
Weber
Multi-component reactions (MCRs) enable the facile, automated and high throughput
generation of small organic molecules. MCRs have been
used to create diversity oriented and biased combinatorial libraries, to
accomplish the synthesis of highly complex natural products as well as for the
large-scale production of drug candidates. This provides medicinal chemists
with a powerful tool to create novel chemical diversity, matching the space of
biological targets with relevant chemistry. The discovery of novel MCRs has become an increasingly active area of research,
yielding novel chemical scaffolds for drug discovery efforts.
[Back to top]
Trends in Virtual Combinatorial
Library Design
Gisbert Schneider
Recent developments in
combinatorial molecular design using virtual screening methods are summarised. These include similarity-based compound
clustering techniques, structure-based docking and scoring, and fragment-based
de novo design. Three major trends have been identified: i)
the design of small targetfocused compound libraries
yielding activity-enriched sets of molecules; ii) advanced prediction methods
for “drug-like” molecular properties complement activity
predictions in the library design process, forming a multi-dimensional
objective function; iii) “cherry picking” of selected products is
increasingly used in lead generation and optimisation
compared to purely educt-driven library design
methods aiming at maximising structural diversity.
[Back to top] Analytical Techniques for Small Molecule
Solid Phase Synthesis
Jan
J. Scicinski, Miles S. Congreve, Corinne Kay and
Steven V. Ley
Although resin-based chemistry
offers many practical advantages over conventional solution phase for the
synthesis of combinatorial libraries, effective monitoring of reactions
conducted on the support remains a challenge. A number of techniques have been
developed to enable the analysis of solid phase organic synthesis either by
monitoring the resin-bound species directly or by the analysis of small
quantities of material cleaved from the support. This review outlines some of
the principles of the various techniques for the analysis of intermediates and
products obtained from solid-phase chemistry.
[Back to top] Natural Product Guided Compound Library
Development
Rolf
Breinbauer, Michael Manger, Michael Scheck and Herbert Waldmann
Natural products are biologically
validated starting points for the design of combinatorial libraries, as they
have a proven record of biological relevance. This special role of natural
products in medicinal chemistry and chemical biology can be interpreted in the
light of new insights about the domain architecture of proteins gained by
structural biology and bioinformatics. In order to fulfil
the specific requirements of the individual binding pocket within a domain
family it is necessary to optimise the natural
product structure by chemical variation. Solid-phase chemistry is becoming an
efficient tool for this optimisation process, and
recent advances in this field are highlighted in this review article.
[Back to top] Polymer-Supported Metal-Phosphine Complexes
for use as Catalysts or Linkers in Medicinally-Oriented Organic Synthesis
Nicholas E. Leadbeater
Polymer-supported catalysts and
reagents have found many uses in synthetic organic chemistry. This review
discusses the preparation of polymer-supported phosphine
ligands and organometallic complexes formed using these and highlights their use in
reactions that are of particular interest to medicinal chemists. The scope of
the review is limited to phosphine ligands and their metal complexes attached to derivitised polystyrene supports.
[Back to top] The Combinatorial Centre of Excellence - A Unique Industrial &
Academic Partnership
Mark Bradley
The Combinatorial Centre of
Excellence (CCE) offers a unique opportunity for the exploitation of a broad
range of combinatorial methodologies. Many areas of activity are under
investigation, including high-throughput X-ray of small molecules, parallel
polymer chemistry and the development of new multi-component reactions.
[Back to top] Accelerating Drug Discovery by Integrative Implementation of Laboratory
Automation in the Work Flow
Matthias Nettekoven and Andrew W. Thomas
Acceleration of the drug
discovery process in pre-clinical pharmaceutical research is a highly desirable
goal and combinatorial chemistry united with automation technology promised to
accomplish this task. Through the accumulation of experience with automated
devices over time it became evident that only by harmonisation
and streamlining of work-flow procedures the efficiency of the overall process
can be improved. An open architecture of efficient data management and
appropriate utilization of automated laboratory protocols provides the
opportunity to react in a flexible and advisable way. Only an integrative
workflow concept promotes the enhancement of the overall performance. However,
the foundation of any efforts towards the accelerated synthesis of new and
desired compound arrays lies in the development of reliable chemistry protocols
amenable to solid- and solution phase chemistry.