Stochastic Proximity Embedding

Although it works well with linear or quasi-linear subspaces, it fails to detect nonlinear structures, curved manifolds, and arbitrarily shaped clusters. Another disadvantage is that MDS attempts to preserve all pairwise distances in the data sample, both local and remote. It has been known for some time that conventional similarity measures, such as the Euclidean distance, tend to underestimate the proximity of points on a nonlinear manifold and lead to erroneous...

Fluorescence Polarization

In FP, the use of polarized light to excite a solution of fluorescent molecules results in preferential excitation of the molecules that have their transition moments (dipoles) parallel to the direction of the polarized light of excitation. The polarization of their emitted light depends upon how fast the fluorescent probes rotate during the lifetime of its excitation state 9 the faster the rotation, the smaller the polarized signal (P). The fluorescent probes usually used in FP possess...

Pharmacophore Analysis

The generation of a diverse set of compounds based on analysis of the pharmacophores they contain is rather more complex, requiring the generation of a pharmacophore fingerprint for all conformations of every molecule in the database. The pharmacophore concept discards the traditional perceptions of chemical structure, Full Parent Database Mean Tanimoto 0.9 Optimal Diverse Subset Mean Tanimoto 0.73 Diverse Subset vs Commercial Database Mean Tanimoto 0.4 Full Parent Database Mean Tanimoto 0.9...

Michael Entzeroth

ISBN-10 0-85404-842-1 ISBN-13 978-0-85404-842-7 A catalogue record for this book is available from the British Library The Royal Society of Chemistry 2006 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by...

Ligand vs Target Detected Methods

NMR screening can be divided into ligand- and target-detected methods. In the first class, changes induced in the ligand's NMR signals by binding to a large target are observed, whereas in the second class, the influences of ligands on the spectra of the target are detected. Both techniques have their intrinsic advantages for different applications, making them largely complementary. Ligand-based methods predominantly make use of one-dimensional (1D) NMR spectra and therefore are comparably...

High Throughput Aliquoting of the HTS Library

The replication of microliter or nanoliter aliquots of compound solutions in DMSO in high-density plates with low well-to-well variability of the aliquot volume is a demanding liquid-handling task. The challenge is set forth by several prerequisites and requirements Because the final DMSO concentration in the assay volume has to be kept low, compound aliquots for HTS and uHTS have a very small volume and are highly concentrated. DMSO is highly hygroscopic, but has to be kept nearly water-free...

Engineered Biosynthesis of Multimodular PKS Products

The differences among the various Type I PKSs that give rise to the diverse aglycons shown in Figure 3 are (1) the specificity of the loading module (2) the number of modules present in the PKS (3) the specificity of the individual AT domain in each module (4) the combinations of reductive domains in each module and (5) the linear combination of modules within a PKS. The modular architecture of Type I PKSs provides a powerful platform for combinatorial biosynthesis through domain shuffling,...

Specificity of Drug Candidates and the Construction of In Vitro Specificity Panels

In the following sections, we focus on the in vitro target screening strategies that are used for monitoring specificity of drug candidates. The first part will concentrate on the target specificity assays for receptors, this section is followed by the bioassay technologies used for kinases, and then finally we illustrate the in vitro methods for ion channel targets. The concept of a receptor as a therapeutic target is central to drug discovery. Receptors sense extracellular chemical signals...

Protein Binding

Once absorbed into the organism, the drug has to reach its site of action where the free concentration of the active material will determine its effect. The free concentration of the drug is modified by the interaction of the compound with proteins, such as human serum albumin (HSA), which decreases the free concentration of the drug available for interaction with the target. Protein binding of drug molecules to plasma or tissue proteins means different things to various people in the drug...

Homogeneous Time Resolved Fluorescence

HTRF is a homogeneous technology which combines an FRET process with time-resolved fluorescence detection to probe biomolecular interactions.27,44 This combination is made possible through the use of a long lifetime fluorescent FRET donor, a lanthanide cryptate. Cryptates are formed by the inclusion of a rare earth ion (e.g. europium) into the 3-dimensional cavity of a ligand called cryptand.3 The cryptand plays the same role as the chelate in the luminescent lanthanide chelates used in DELFIA...

Combinatorial Biosynthesis of Type II Polyketides

The Type II PKS modules that can be reshuffled to introduce structural diversity among aromatic polyketides include (1) the initiation module which specifies the starter unit (2) the elongation module which determines chain length (3) the immediate tailoring enzymes that dictate the oxidation state at C9 and the C-C connectivity during cyclization and (4) the downstream tailoring enzymes. Systematic recombination of PKS genes from different clusters has provided insights into the substrate...

References

Martina and F. Quartieri, Use of multicomponent, domino, and other one-pot syntheses on solid phase powerful tools for the generation of libraries of diverse and complex compounds, Comb. Chem. High Throughput Screening, 2003, 6(7), 693. (ii) N.A. Boyle and K.J. Janda, Formats for combinatorial synthesis solid-phase, liquid-phase and surface, Curr. Opin. Chem. Bio., 2002, 6(3), 339. (iii) T. Carell, E.A. Wintner, A.J. Sutherland, J. Rebek Jr., Y.M. Dunayevskiy and P....

Fully Automated PASP Synthesis of Drug Like Molecules in Batch Mode

Recently, a number of publications have dealt with the synthesis of drug-like molecules via fully automated PASP auto-PASP synthesis. This scenario entails the use of a series of immobilised reagents and scavenger reagents to perform a variety of sequential synthetic transformations in a common solvent. Each of the transformations required can be automated using a commercially available robotic synthesiser. The first auto-PASP synthesis described was the preparation of a 36-membered array of...

Topological Polar Surface Area tPSA and Blood BrainBarrier Permeability Log BB

These two functions are not truly independent parameters, since both correlate with the compound's log P value. Indeed, Log BB has also been calculated using PSA alone, as well as several other solvation and free energy methods.22-24 After Young showed that experimental Log P values could be correlated with experimental Log BB data25 algorithms were developed to calculate Log BB based on tPSA and c Log P c Log P is a computed Log P value, based on a calculation of the contributions of the...

Peptide and Nucleotide Libraries Redux

We began by describing peptides and nucleotides, the first classes of compounds to be prepared combinatorially. Both of these suffer from some disadvantages for classical drug discovery, as alluded to earlier. Nevertheless, when used creatively, peptide libraries can be a valuable resource for medicinal chemistry and the discovery of novel leads. An impressive recent development is the synthesis of mixture-based peptide libraries containing motifs for protease inhibition. These libraries can...

Fluorous Mixture Synthesis

A highly relevant development of the light fluorous approach for parallel synthesis and library production is the fluorous mixture synthesis FMS strategy by Curran.118 FMS offers an alternative that combines the positive aspects of homogeneous kinetics with agreeable and practical separation protocols. While solid-phase mixture techniques split-pool intermingle beads or containers, they do not mix compounds. The corresponding solution-phase mixture strategies often have the disadvantage that...