Combinatorial Chemistry & High Throughput Screening - Volume 7, Issue 5, 2004

This Combinatorial Chemistry and High-Throughput Screening compilation covers an array of diverse topics. The topics range from novel basic methods for synthesis, to gene-family targeted libraries, to pure design criteria, to dendrimers for gene delivery. New technologies discussed here, such as Microwave Chemistry and microreactors, as with the field of highthroughput chemistry, will establish their niches, becoming mo Read More

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.

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 lig Read More

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 variou Read More

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 transf Read More

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 p Read More

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 Read More

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 ho Read More

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 ex Read More

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 r Read More

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 r Read More