Combinatorial Chemistry & High
Throughput Screening, Vol. 7, No. 5, 2004
Contents
Designing Targeted Libraries
Guest Editors: Guillermo A. Morales / Barry
A. Bunin
Combinatorial
Synthesis in Micro Reactors Pp.397-405
P.
Watts and S.J. Haswell
Selection,
Application, and Validation of a Set of Molecular Descriptors for Nuclear
Receptor Ligands Pp.407-412
Eugene
L. Stewart, Peter J. Brown, James A. Bentley and Timothy M. Willson
Synthesis
of a 2, 4, 8-Trisubstituted Pyrimidino[5, 4-d]Pyrimidine Library via
Sequential SNAr Reactions on Solid-Phase Pp.413-421
Polyplexes
and Lipoplexes for Mammalian Gene Delivery: From Traditional to Microarray
Screening Pp.423-430
S.E.
How, B. Yingyongnarongkul, M.A. Fara, J.J. Diaz-Mochon, S. Mittoo and M.
Bradley
Structural
Genomics on Membrane Proteins: Mini Review Pp.431-439
K.
Lundstrom
The
Selection and Design of GPCR Ligands: From Concept to the Clinic Pp.441-452
Mark
Ashton, Michael H. Charlton, Matthias K. Schwarz, Russell J. Thomas and Mark Whittaker
Creating
Chemical Diversity to Target Protein Kinases Pp.453-472
B.
Li, Y. Liu, T. Uno and N. Gray
Privileged
Structures: Applications in Drug Discovery Pp.473-493
R.W.
DeSimone, K.S. Currie, S.A. Mitchell, J.W. Darrow and D.A. Pippin
The Different Strategies for Designing GPCR and Kinase
Targeted Libraries Pp.495-510
J.F.
Lowrie, R.K. Delisle, D.W. Hobbs and D.J. Diller
Microwave-Promoted
Organic Synthesis Using Ionic Liquids: A Mini Review Pp.511-528
Nicholas
E. Leadbeater, Hanna M. Torenius and Heather Tye
Abstracts
[Back to top] Combinatorial
Synthesis in Micro Reactors
P.
Watts and S.J. Haswell
This article reviews the current and future applications of micro reactors in the field of combinatorial chemistry and drug discovery. Liquid phase reactions have been used to illustrate the advantages of performing chemical reactions in micro reactors which illustrate that reactions can be performed very rapidly in high yield to enable the preparation of combinatorial libraries of structurally related compounds.
[Back to top] Selection, Application, and Validation
of a Set of Molecular Descriptors for Nuclear Receptor Ligands
Eugene
L. Stewart, Peter J. Brown, James A. Bentley and Timothy M. Willson
A methodology for the selection and validation of nuclear receptor ligand chemical descriptors is described. After descriptors for a targeted chemical space were selected, a virtual screening methodology utilizing this space was formulated for the identification of potential NR ligands from our corporate collection. Using simple descriptors and our virtual screening method, we are able to quickly identify potential NR ligands from a large collection of compounds. As validation of the virtual screening procedure, an 8, 000-membered NR targeted set and a 24, 000-membered diverse control set of compounds were selected from our inhouse general screening collection and screened in parallel across a number of orphan NR FRET assays. For the two assays that provided at least one hit per set by the established minimum pEC50 for activity, the results showed a 2-fold increase in the hit-rate of the targeted compound set over the diverse set.
[Back to top] Synthesis of
a 2, 4, 8-Trisubstituted Pyrimidino[5, 4-d]Pyrimidine Library via
Sequential SNAr Reactions on Solid-Phase
M.
El-Araby, R.S. Pottorf and M.R. Player
A solid-phase synthesis of 2, 4, 8-substituted pyrimidino[5, 4-d]pyrimidines involving three controlled SNAr reactions has been developed. Exploration of different heterocyclic starting materials and resin-bound intermediates is highlighted. The preferred method starts with the treatment of resin-bound anilines with 2, 4, 8-trichloropyrimidino[5, 4-d]pyrimidine. This intermediate is subsequently treated with various amines in two steps to yield the final products. The scope of each diversity step was determined and a library of 16, 000 compounds was synthesized.
[Back to top] Polyplexes and Lipoplexes for Mammalian Gene Delivery: From Traditional
to Microarray Screening
S.E. How, B. Yingyongnarongkul, M.A. Fara, J.J. Diaz-Mochon, S. Mittoo and M. Bradley
Gene therapy requires the development of non-toxic and highly efficient delivery systems for DNA and RNAi. Polycations, especially dendrimers, have shown enormous potential as gene transfer vehicles, displaying minimal toxicity with a broad range of cell lines. In this paper, a total of 13 dendrimers, up to G3.0, were constructed from AB3 type isocyanate monomers using solid phase methodology and evaluated for transfection activity. Among the library of compounds prepared, a G3.0 dendrimer displayed comparable activity to Superfect. Gel retardation assays demonstrated that all of the compounds completely bound plasmid DNA, indicating the efficient formation of complexes between DNA and the dendrimers. A “transfection microarray” approach was developed for screening these compounds as well as a panel of lipoplexes (complexes of DNA with cationic lipids) and polyplexes (complexes of DNA with synthetic polycationic polymers), in 3D solution like micro-assay). Five cationic lipids with a cholesterol tail showed stronger or comparable transfection activity relative to Effectene. The new, micro-array screening method was rapid and miniaturized, offering the potential of high throughput screening of large libraries of transfection candidates, with thousands of library members per array, and the ability to rapidly screen a broad range of cell types.
[Back to top] Structural Genomics on Membrane Proteins: Mini Review
K.
Lundstrom
Structural genomics, structure-based analysis of gene products, has so far mainly concentrated on soluble proteins because of their less demanding requirements for overexpression, purification and crystallisation compared to membrane proteins. This so-called “low-hanging fruit” approach has generated more than 25,000 structures deposited in databases. In contrast, the substantially more complex membrane proteins, in relation to all steps from overexpression to high-resolution structure determination, represent less than 1% of available crystal structures. This is in sharp contrast to the importance of this type of proteins, particularly G protein-coupled receptors (GPCRs), as today 60-70% of the current drug targets are based on membrane proteins. The key to improved success with membrane protein structural elucidation is technology development. The most efficient approach constitutes parallel studies on a large number of targets and evaluation of various systems for expression. Next, high throughput format solubilisation and refolding screening methods for a wide range of detergents and additives in numerous concentrations should be established. Today, several networks dealing with structural genomics approaches of membrane proteins have been initiated, among them the Membrane Protein Network (MePNet) programme that deals with the pharmaceutically important mammalian GPCRs. In MePNet, three overexpression systems have been employed for the evaluation of 101 GPCRs, which has generated large quantities of numerous recombinant GPCRs, compatible for structural biology applications.
[Back to top] The Selection and Design of GPCR Ligands: From Concept to the
Clinic
Mark
Ashton, Michael H. Charlton, Matthias K. Schwarz, Russell J. Thomas and Mark
Whittaker
Virtual screening methods using structure-based, pharmacophore-based and descriptor based protocols may be used to identify ligands for the G-protein coupled receptor target family. A complementary approach is the synthesis and screening of compound libraries designed using privileged motifs and/or based on validated hit molecules. A virtual screening approach based on molecular docking performed with GOLD using a templated homology model and a consensus scoring procedure can identify vasopressin 1a receptor antagonists. In a separate project a library design and synthesis approach based around validated hit GPCR ligands led to the identification of potent oxytocin antagonists. Subsequent optimisation of the initial library
compounds has provided compounds that are now being evaluated in the clinic for the treatment of preterm labour.
[Back to top] Creating Chemical Diversity to Target Protein Kinases
B.
Li, Y. Liu, T. Uno and N. Gray
Protein kinases play crucial roles in regulating virtually every cellular process and are currently attracting tremendous interest as drug targets from the pharmaceutical industry. The major challenges facing the development of the potential kinase inhibitor drugs are: selectivity, physical properties (solubility, molecular weight), and pharmacological properties (bioavailability, half life, toxicity, etc.) This review focuses on how selective protein kinase inhibitors that target the ATP and allosteric binding sites are currently being identified and optimized.
[Back to top]
Privileged Structures: Applications in Drug Discovery
R.W.
DeSimone, K.S. Currie, S.A. Mitchell, J.W. Darrow and D.A. Pippin
Over the past 15 years the privileged structure concept has emerged as a fruitful approach to the discovery of novel biologically active molecules. Privileged structures are molecular scaffolds with versatile binding properties, such that a single scaffold is able to provide potent and selective ligands for a range of different biological targets through modification of functional groups. In addition, privileged structures typically exhibit good drug-like properties, which in turn leads to more drug-like compound libraries and leads. The net result is the production of high quality leads that provide a solid foundation for further development. The identification of privileged structures will be discussed, emphasizing the importance of understanding the structure-target relationships that confer “privileged” status. This understanding allows privileged structure based libraries to be targeted at distinct target families (e.g. GPCRs, LGIC, enzymes/kinases). Privileged structures have been successfully exploited across and within different target families and promises to be an effective approach to the discovery and optimization of novel bioactive molecules. The application of the privileged structure approach, both in traditional medicinal chemistry and in
the design of focused libraries, will be discussed with the aid of illustrative examples.
[Back to top] The Different
Strategies for Designing GPCR and Kinase Targeted Libraries
J.F.
Lowrie, R.K. Delisle, D.W. Hobbs and D.J. Diller
In recent years the trend in combinatorial library design has shifted to include target class focusing along with diversity and drug-likeness criteria. In this manuscript we review the computational tools available for target class library design and highlight the areas where they have proven useful in our work. The protein kinase family is used to illustrated structure-based target class focused library design, and the G-protein coupled receptor (GPCR) family is used to illustrate ligand-based target class focused library design. Most of the tools discussed are those designed for libraries targeted to a single protein and are simply applied “bruteforce” to a large number of targets within the family. The tools that have proven to be the most useful in our work are those that can extract trends from the computational data such as docking and clustering or data mining large amounts of structure activity or high throughput screening data. Finally, areas where improvements are needed in the computational tools available for target class focusing are highlighted. These areas include tools to extract the relevant patterns from all available information for a family of targets, tools to efficiently apply models for all targets in the family rather than just a small subset, mining tools to extract the relevant information from the computational absorption, distribution, metabolism, excretion and toxicity (ADMET) and targeting data, and tools to allow interactive exploration of the virtual space around a library to facilitate the selection of the library that best suits the needs of the design team.
[Back to top] Microwave-Promoted
Organic Synthesis Using Ionic Liquids: A Mini Review
Nicholas
E. Leadbeater, Hanna M. Torenius and Heather Tye
Due to their extraordinary properties, such as the ionic composition, good thermal stability, low vapor pressure, and solution interactions, ionic liquids can be used as solvents, reagents, and heating aids in conjunction with microwave chemistry. Synthesis of diverse molecules can be improved with the use of the ionic liquids assisted microwave heating due to fast reaction times, simple reaction work-up, and catalyst recovery. This mini-review outlines this newly emerging field.