Combinatorial Chemistry & High Throughput Screening - Volume 5, Issue 1, 2002

Phage display has become a widely used tool for the identification of proteins or peptides with affinity for a variety of biomolecules. The versatility, simplicity and cost effectiveness of this application has pervaded a wide variety of research areas. Although not without its limitations, phage display has provided a convenient methodology for obtaining ligands to study the function, structure and diagnostic or therapeutic poten Read More

Antigen recognition by antibodies or ligand-receptor interactions involve small areas of the molecule named epitopes that are normally conformational in nature. The availability of combinatorial peptide libraries has provided a powerful tool for selecting novel sequences which mimic conformational epitopes (mimotopes) either structurally and / or immunologically. These mimotopes can be particularly useful in a num Read More

There is a continuing need for increased throughput in the evaluation of new chemical entities in terms of their pharmacokinetic (PK) parameters as part of new drug discovery. This review summarizes various approaches that have been used to increase throughput in this area. The article divides the approaches into two areas: assay enhancement and sample reduction.

A library with 63 paclitaxel analogues modified at the C10 position of paclitaxel has been prepared using parallel solution phase synthesis. Most of the C10 analogues were slightly less active than paclitaxel in the tubulin assembly assay and had reduced potency in the B16 melanoma and MCF-7 cell line cytotoxicity assays. These modifications at C10, however, did not lead to the total loss of activity, indicating that the C10 moiety Read More

The present study introduces a new strategy of selection of a maximum diversity sample of n compounds from N available in a molecular database. This strategy can be useful in pharmacological screening, combinatorial chemistry or parallel synthesis planning. It consists of first describing the compounds by means of parameters derived from quantum mechanical computations (water solvation ΔG, benzene solv Read More

A pulsed ultrafiltration-mass spectrometric screening method has been developed to evaluate the metabolic stability of drugs. Pooled human liver microsomes containing cytochrome P450 enzymes were trapped by an ultrafiltration membrane in a stirred flow-through chamber, and eight β-blocker drugs including acebutolol, alprenolol, atenolol, metoprolol, oxprenolol, pindolol, propranolol, and timolol were flow-injected thro Read More

A pulsed ultrafiltration cell with a 35 μL binding chamber was evaluated for its ability to screen ligands that formed non-covalent complexes with protein targets. The cell was tested with ligands to the targets of carbonic anhydrase and serum albumin. Non-covalent ligand binding to both of these targets was observed and bound ligands were eluted from the cell in less than five min. The cell was also demonstrated to effectiv Read More

An efficient parallel synthesis of 6,7-dimethoxytetrahydroisoquinolines is reported. The key reaction step is 3,4-dimethoxyphenethylimines reacting with acid chlorides to form an N-acyliminium ion intermediate, which undergoes Pictet-Spengler condensation to give the desired products in >80 percent yield. Both solution-phase and solid-phase synthesis of 6,7-dimethoxytetrahydroisoquinolines are described.

Using a combinatorial peptide library that is based on the one-bead one-peptide approach we identified 14 peptide substrates for the c-ABL protein tyrosine kinase, which define three distinct consensus sequence groups. This is distinct from many serine / threonine kinases, which often phosphorylate only one major consensus sequence. The three consensus sequences accurately predict phosphorylation sites in cellular Read More

A new pyrimidine based scaffold has been identified for generation of combinatorial libraries using solid phase technique.The utility of the scaffolds was demonstrated by synthesizing small libraries of 12 substituted pyrimidines (4a-4l).