References

Guida, The art and practise of structure based drug design, Med. Res. Rev., 1996, 16(1), 3-50. 2. M.M. Hann and T.I. Oprea, Pursuing the leadlikeness concept in pharmaceutical research, Current Opinion in Chemical Biology, 2004, 8, 255-263. 3. K.S. Lam, S.E. Salmon, E.M. Hersh, V.J. Hruby, W.M. Kazmierski and R.J. Knapp, A new type of synthetic peptide library for identifying ligand-binding activity, Nature, 1991, 354(6348), 82-84. 4. W.A. Warr, The Directory...

Fluorous Phase Techniques 41 General

Even if several groups have been active in the development of fluorous techniques, many of the early, seminal papers were presented by just a few groups, most notably Horvath, Gladysz, and Curran.6,7 In the last few years several excellent reviews have R-N3 + E+ -4---R-NHR' R' COOEt, Cbz R alkyl, aryl U trasound Boc, tosyl, SO2Ph conventional 41 h, 82 ultrasound 2 h, 88 conventional 41 h, 82 ultrasound 2 h, 88 also been published by Zhang.888-90 The physical and chemical bases behind the...

PKa

The ionization of monoprotic acids and bases and hence their solubility and absorption is dependent on their p a, the pH at which the drug is 50 ionized. First developed by Hammett and published in 1940,26 the relation between the dissociation constants of benzoic acid derivatives and the longer range electronic (inductive, mesomeric and field) effects is linear and additive. In this equation, pKa0 is the pKa of the unsubstituted molecule, O refers to the constant assigned to a respective...

Commercial Offerings

There are many sources of commercially available small molecules. Some of those sources would acknowledge that not all of the molecules they offer are suitable as potential pharmaceutical materials and that many more could only be considered as reagents or intermediates. However, there are still a very large number of providers giving access to high quality small molecules which may be considered good candidates for hit-to-lead or lead optimisation chemistry, should they be identified as a hit...

Sample Management for HTS and Multidimensional Compound Profiling

Modern high-throughput synthesis methods deliver compounds in low-milligram quantities. Depending on the degree of assay miniaturization, this amount of material is sufficient for 1000 to 10,000 HTS projects. The size of the compound collections of pharmaceutical companies ranges from several hundred thousands to more than one million compounds. The vast number of samples processed in HTS are prepared and distributed in a staggered process, involving several consecutive sample transfer and...

Hit Optimization

For hit optimization, the confirmed hits from the validation process are first ranked and clustered. Specific properties, e.g. Lipinski's rule of five, have to be considered to develop a promising lead structure (Table 1).13,41 This assessment includes the solubility, molecular weight, chemical accessibility, and affinities (binding constants). For a further improvement of the binders, structural information is indispensable.15 The exact binding site as well as the precise binding mode has to...

Origin of Biologically Active Peptides

Organisms from all species produce a huge variety of peptides in order to respond to certain physiological or pathophysiological stimuli. Reflecting their many different functions, their molecular structures are extremely diverse, ranging from very short peptides such as the enkephalins to complex peptide hormones like insulin with 51 amino acids in two chains connected by two disulfide bonds. Also very similar to peptides occurring in nature are active peptides identified from the primary...

Conclusion

In this chapter, we have attempted to provide the reader with descriptions of a few methods that define and quantify chemical diversity. The basic elements involved in chemical diversity definition include a measure of distance between molecules, a measure of molecular diversity that realistically quantifies the diversity of a set of compounds, and a sampling or selection method for identifying a diverse subset of compounds from large libraries. Although conceptually simple, molecular diversity...

Fluorous Protecting Groups

The development of fluorous protecting groups has attracted a lot of interest. This stems partly from the ubiquitous need for protecting groups, but also because the use of a fluorous protecting group offers a convenient way to introduce the desired fluo-rous label, which later can be removed as a natural part of the synthetic scheme. The scope of this chapter does not allow a thorough discussion of the different protecting groups, hence the reader is advised to consult the well-written reviews...

Distance Based Metrics

Distance-based metrics quantify the diversity of a set of compounds as a function of their pairwise (dis)similarities in a descriptor space.7,8 It is important to mention that distance coefficients are analogous to distances in multidimensional geometric space, although they are usually not equivalent to such distances. For a distance coefficient to be described as a metric, it must possess the following four properties9 (1) Distance values must be nonzero and the distance from an object to...

Subset Selection and Classification

Exhaustive assaying of all compounds in a large collection is usually impossible due to restrictions on time and resources. It is desirable, if not necessary, for subset selection to be made rationally. A subset that maximizes the information content of the entire library and increases chance of finding an active compound or series is clearly preferred. The selection, or library design, can be carried out at the reagent or product level. In either case, an efficient algorithm is required to...

Enzyme Fragment Complementation

This technology uses complementation of P-galactosidase fragments to generate a fluorescent or a chemiluminescent signal. When a small a fragment peptide of 4 kDa called ProLabel interacts with an ra-deletion mutant of the enzyme (called Enzyme Acceptor), an active tetrameric form of the P-galactosidase results.11 The active enzyme can generate a signal by hydrolysing fluorescent substrates like 4-methy-lumbelliferyl P-D-galactopyranoside (4-MUG) or Resofurin, or other luminescent substrates....

Preface

The methods of drug discovery in the pharmaceutical industry have changed dramatically in the last two decades. By the late 1980s, a strong belief had emerged that drug development is purely a numbers game, with anticipated drop-out rates at each stage of the process such that only one compound out of 10,000 synthesized would survive to make it to the market. Technologies to accelerate both synthesis and screening were developed and adopted by virtually every pharmaceutical and biotech research...

Improvements in Synthetic Methods

Novel approaches to synthetic organic chemistry are indeed among the core processes for new library developments, as addressed in Chapters 3 and 4 in this volume. Significant advances in the way that chemical reactions are carried out, whether in solution or on solid phase,1 in traditional glassware or state-of-the-art reactors,2 in step-wise fashion or as multicomponent reactions1,3 are continuously being developed, improved and adapted to the production of libraries. The expansion of...

Focused Libraries The Evolution in Strategy from Large Diversity Libraries to the

2 A Synergistic, Multidisciplinary Approach to 2.1 Improvements in Synthetic Methods 164 2.2 Impact of In Silico Tools for Library Design 165 2.3 Influence of Biology in Library Design 166 3 Library Design Concepts 167 3.1 Impact of Diversity on Library Design 167 3.2 Diversity-Oriented Synthesis in Prospecting Library Design 168 3.3 Target-Oriented Library Design 168 3.4 Focus on Drug-Like Libraries 170 4.1 Libraries Focused on Pharmacophore Models 170 4.2 Libraries Focused on Privileged...

Pipetting and Dispensing in High Density Plates

In ultra-high-throughput screening (uHTS) with more than 100,000 assays per day and an assay volume that is in the ideal case below 10 L, liquid handling tends to be the rate limiting step and the pacemaker of the screening process. Parallel processing of (at least) 384 wells in 384- or 1536-well plates is vital to achieve ultrahigh throughput. Most assays in high-density plates employ microliter or nanoliter liquid-handling operations to transfer compound aliquots from sample plates to assay...

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...

Fully Automated PASP Synthesis of Drug Like Molecules in Batch Mode

Tfp Polymer

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...