Extremal problems for topological indices in combinatorial chemistry.

Topological indices of molecular graphs are related to several physicochemical characteristics; recently, the inverse problem for some of these indices has been studied, and it has some applications in the design of combinatorial libraries for drug discovery. It is thus very natural to study also extremal problems for these indices, i.e., finding graphs having minimal or maximal index. In this paper, these questions will be discussed for three different indices, namely the sigma-index, the c-index and the Z-index, with emphasis on the sigma-index.     

Combinatorial biochemistry in plants: the case of O-methyltransferases

Combinatorial chemistry is common place today in chemical synthesis. Virtually thousands of derivatives of a molecule can be achieved by automated systems. The use of biological systems to exploit combinatorial chemistry (combinatorial biochemistry) now has multiple examples in the polyketide field. The modular functional domain structure of polyketide synthases have been recombined through genetic engineering into unnatural constellations in heterologous hosts in order to produce polyketide structures not yet discovered in nature. We present herein an example for a potential type of combinatorial biochemistry in alkaloidal systems using various combinations of Thalictrum tuberosum (meadow rue) O-methyltransferase subunits that result in heterodimeric enzymes with substrate specificities that differ from those of the homodimeric native enzymes.     

Combinatorial chemistry,automation and molecular diversity: new trends in the pharmaceutical industry

Combinatorial chemistry has emerged as a set of novel strategies for the synthesis of large sets of compounds (combinatorial libraries) for biological evaluation. Within a few years combinatorial chemistry has undergone a series of changes in trends, which are closely related to two important factors in libraries: numbers and quality. While the number of compounds in a library may be easily expressed, it is a lot more difficult to indicate the degree of quality of a library. This degree of quality can be split into two aspects : purity and diversity. The changing trends in combinatorial chemistry with respect to the strategies, the technologies, the libraries themselves (numbers and purity aspects) and the molecular diversity are outlined in this paper.     

Computational Chemistry in Lead Identification,Library Design and Lead Optimisation

Abstract

We describe a variety of the computational techniques which we use in the drug discovery and design process. Some of these computational methods are designed to support the new experimental technologies of high-throughput screening and combinatorial chemistry. We also consider some new approaches to problems of long-standing interest such as protein-ligand docking and the prediction of free energies of binding.     

Computational bioinorganic chemistry. Part III. The tools of the trade: from high-level ab initio calculations to structural bioinformatics

Having long focused on the electronic-structural aspects of metalloenzymes and their synthetic models, Abhik is currently exploring a number of synthetic problems related to self-assembly processes, dynamic combinatorial libraries, and fluorine chemistry.     

Diketopiperazines in peptide and combinatorial chemistry.

Diketopiperazines (DKPs), the smallest cyclic peptides, represent an important class of biologically active natural products and their research has been fundamental to many aspects of peptide chemistry. The advent of combinatorial chemistry has revived interest in DKPs for two reasons: firstly, they are simple heterocyclic scaffolds in which diversity can be introduced and stereochemically controlled at up to four positions; secondly, they can be prepared from readily available alpha-amino acids using very robust chemistry. Here synthetic methods, conformation, as well as applications of DKPs are summarized and discussed critically.     

'One bead two compound libraries' for detecting chemical and biochemical conversions

When combinatorial chemistry was introduced 13 years ago, the expectations were high for the delivery of results, particularly in the pharmaceutical industry. However, combinatorial chemistry was implemented independently of the application for which the products were going to be used. Resins developed only for efficient solid-phase synthesis were used and products were employed in existing assays developed for traditional solution studies. There was almost no assay or technology development and the use of real combinatorial methods soon had to give way to high-throughput synthesis and traditional screening. However, during recent years more sophisticated resins and assay techniques have been developed that may result in a second and more successful implementation of real integrated combinatorial chemistry. The first in this line of new developments is the 'one bead two compound' assay, in which the resin bead in addition to a combinatorial library member contains a reporter compound that can act as a beacon to monitor the activity of the library member. This powerful concept can be generally applied in all fields of combinatorial chemistry including drug, catalysts and material development.     

Parallel and combinatorial approaches for synthesis of ligands

Although new detection screening methods must still be developed, the actual main limitation in combinatorial chemistry seems to be the diversity of ligands that can be generated in terms of real structural and chemical diversity. Thus, there is a strong interest for the development of different strategies for the parallel or combinatorial synthesis of ligands. We report here a selection of recent attempts proposing 'open' approaches able to increase the diversity of molecular architecture truly accessible via parallel or combinatorial processes.     

Discovery of an Aurora kinase inhibitor through site-specific dynamic combinatorial chemistry

We demonstrate a fragment-based lead discovery method that combines site-directed ligand discovery with dynamic combinatorial chemistry. Our technique targets dynamic combinatorial screening to a specified region of a protein by using reversible disulfide chemistry. We have used this technology to rapidly identify inhibitors of the drug target Aurora A that span the purine-binding site and the adaptive pocket of the kinase. The binding mode of a noncovalent inhibitor has been further characterized through crystallography.     

Ligands for kappa-opioid and ORL1 receptors identified from a conformationally constrained peptide combinatorial library.

We have screened a synthetic peptide combinatorial library composed of 2 x 10(7) beta-turn-constrained peptides in binding assays on four structurally related receptors, the human opioid receptors mu, delta, and kappa and the opioid receptor-like ORL1. Sixty-six individual peptides were synthesized from the primary screening and tested in the four receptor binding assays. Three peptides composed essentially of unnatural amino acids were found to show high affinity for human kappa-opioid receptor. Investigation of their activity in agonist-promoted stimulation of [(35)S]guanosine 5'-3-O-(thio)triphosphate binding assay revealed that we have identified the first inverse agonist as well as peptidic antagonists for kappa-receptors. To fine-tune the potency and selectivity of these kappa-peptides we replaced their turn-forming template by other turn mimetic molecules. This "turn-scan" process allowed the discovery of compounds with modified selectivity and activity profiles. One peptide displayed comparable affinity and partial agonist activity toward all four receptors. Interestingly, another peptide showed selectivity for the ORL1 receptor and displayed antagonist activity at ORL1 and agonist activity at opioid receptors. In conclusion, we have identified peptides that represent an entirely new class of ligands for opioid and ORL1 receptors and exhibit novel pharmacological activity. This study demonstrates that conformationally constrained peptide combinatorial libraries are a rich source of ligands that are more suitable for the design of nonpeptidal drugs.     

Mesofluidic devices for DNA-programmed combinatorial chemistry

Hybrid combinatorial chemistry strategies that use DNA as an information-carrying medium are proving to be powerful tools for molecular discovery. In order to extend these efforts, we present a highly parallel format for DNA-programmed chemical library synthesis. The new format uses a standard microwell plate footprint and is compatible with commercially available automation technology. It can accommodate a wide variety of combinatorial synthetic schemes with up to 384 different building blocks per chemical step. We demonstrate that fluidic routing of DNA populations in the highly parallel format occurs with excellent specificity, and that chemistry on DNA arrayed into 384 well plates proceeds robustly, two requirements for the high-fidelity translation and efficient in vitro evolution of small molecules.     

Automated synthesis and combinatorial chemistry

The advent of combinatorial chemistry for the high-throughput synthesis of compounds has driven the advancement of new and emerging technologies for synthetic chemistry laboratories. Automated methods for reaction design, information management, chemical synthesis, compound analysis, and biological testing are necessary to realize the full potential of combinatorial chemistry efforts.     

Microfluidic combinatorial chemistry

Microreactors are finding increasing application in the field of combinatorial chemistry. In the past few years, microreactor chemistry has shown great promise as a novel method on which to build new chemical technology and processes. It has been conclusively demonstrated that reactions performed within microreactors invariably generate relatively pure products in high yield. One of the immediate and obvious applications is therefore in combinatorial chemistry and drug discovery.     

Using Fish Communities to Assess Streams in Romania: Initial Development of an Index of Biotic Integrity*

Multimetric biotic indices increasingly are used to complement physicochemical data in assessments of stream quality. We initiated development of multimetric indices, based on fish communities, to assess biotic integrity of streams in two physiographic regions of central Romania. Unlike previous efforts to develop such indices for European streams, our metrics and scoring criteria were selected largely on the basis of empirical relations in the regions of interest. We categorised 54 fish species with respect to ten natural-history attributes, then used this information to compute 32 candidate metrics of five types (taxonomic, tolerance, abundance, reproductive, and feeding) for each of 35 sites. We assessed the utility of candidate metrics for detecting anthropogenic impact based on three criteria: (a) range of values taken, (b) relation to a site-quality index (SQI), which incorporated information on hydrologic alteration, channel alteration, land-use intensity, and water chemistry, and (c) metric redundancy. We chose seven metrics from each region to include in preliminary multimetric indices (PMIs). Both PMIs included taxonomic, tolerance, and feeding metrics, but only two metrics were common to both PMIs. Although we could not validate our PMIs, their strong association with the SQI in each region suggests that such indices would be valuable tools for assessing stream quality and could provide more comprehensive assessments than the traditional approaches based solely on water chemistry.     

Solving chemical problems through the application of evolutionary principles

Molecular evolution has been widely applied in the laboratory to generate novel biological macromolecules. The principles underlying evolution have more recently been used to address problems in the chemical sciences, including the discovery of functional synthetic small molecules, catalysts, materials and new chemical reactions. The application of these principles in dynamic combinatorial chemistry and in efforts involving small molecule-nucleic acid conjugates has facilitated the evaluation of large numbers of candidate structures or reactions for desired characteristics. These early efforts suggest the promise of pairing evolutionary approaches with synthetic chemistry.     

Action Potential Duration Heterogeneity of Cardiac Tissue Can Be Evaluated from Cell Properties Using Gaussian Green's Function Approach

Action potential duration (APD) heterogeneity of cardiac tissue is one of the most important factors underlying initiation of deadly cardiac arrhythmias. In many cases such heterogeneity can be measured at tissue level only, while it originates from differences between the individual cardiac cells. The extent of heterogeneity at tissue and single cell level can differ substantially and in many cases it is important to know the relation between them. Here we study effects from cell coupling on APD heterogeneity in cardiac tissue in numerical simulations using the ionic TP06 model for human cardiac tissue. We show that the effect of cell coupling on APD heterogeneity can be described mathematically using a Gaussian Green''s function approach. This relates the problem of electrotonic interactions to a wide range of classical problems in physics, chemistry and biology, for which robust methods exist. We show that, both for determining effects of tissue heterogeneity from cell heterogeneity (forward problem) as well as for determining cell properties from tissue level measurements (inverse problem), this approach is promising. We illustrate the solution of the forward and inverse problem on several examples of 1D and 2D systems.     

Efficient discovery of inhibitory ligands for diverse targets from a small combinatorial chemical library of chimeric molecules

Living systems are mainly composed and regulated by compounds in four biochemical classes and their polymers-nucleotides, carbohydrates, lipids, and amino acids. Early combinatorial chemistry libraries consisted of peptides. The present report describes the general bioactivity and biophysical properties of a combinatorial chemical library that used glyco, nucleotidyl, and lipid building blocks. The resulting chimeric combinatorial library of 361 compounds had a confirmed cumulative hit rate of 0.16%, which is 8-fold higher than a commonly claimed industrial benchmark of 0. 02%. It produced 7 structurally confirmed hits for a third of 12 proprietary drug discovery projects, and these comprised a variety of molecular targets. Diversity analyses demonstrated that despite the small number of compounds, a wider range of diversity space was covered by this library of biochemical chimeras than by a branched tripeptide library of the same size and similar generic formula.     

Optimization of chemical libraries by neural networks

Neural networks are finding ever-more applications in the design of combinatorial libraries. These can be divided into two types: Kohonen (self-organizing) maps, and feed-forward networks. While the number of applications is currently quite limited, a rapid increase in publications in this area can be expected in the next few years from the rapid development of general combinatorial chemistry technology.     

Modification of constrained peptides by ring-closing metathesis reaction

Ring-closing metathesis (RCM) with alpha,alpha-diallylglycyl peptides is shown to furnish alpha,alpha-cyclopentenylglycyl peptides as conformationally restrained analogues in the form of post-translational type peptide modification suitable for both peptidomimetic and combinatorial chemistry applications.     

The chemical-biological interface: developments in automated and miniaturised screening technology

The rapidly changing developments in genomics and combinatorial chemistry, generating new drug targets and large numbers of compounds, have caused a revolution in high-throughput screening technologies. Key to this revolution has been the introduction of robotics and automation, together with new biological assay technologies (e.g., homogeneous time resolved fluorescence). With ever increasing workloads, together with economic and logistical constraints, miniaturisation is rapidly becoming essential for the future of high-throughput screening and combinatorial chemistry. This is evident from the introduction of high-density microtitre plates, small volume liquid handling robots and associated detection technology.