Use of Molecular Recognition To Drive Chemical Evolution: Mechanisms of an Automated Genetic Algorithm Implementation

Елисеев, А. В.; Nelen, Marina I.

doi:10.1002/(sici)1521-3765(19980515)4:5<825::aid-chem825>3.0.co;2-7

Cited by 68 publications

(45 citation statements)

References 62 publications

(13 reference statements)

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“…Dynamic libraries can also be of configurational or conformational character, for example in cis,trans isomerisation, in which the difference in configuration can be used in the selection process. [12,13] Carbohydrate recognition plays an important role in many biological processes, such as cell ± cell interactions, cell communication, etc. [14±16] In addition, a multitude of enzymes are involved in various carbohydrate-mediated processes associated with, for example, defence, cell proliferation, and cell death, as well as in general carbohydrate metabolism.…”

Section: Introductionmentioning

confidence: 99%

In Situ Generation and Screening of a Dynamic Combinatorial Carbohydrate Library against Concanavalin A

2000

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Dynamic combinatorial chemistry (DCC) is a recently introduced approach that is based on the generation of combinatorial libraries by reversible interconversion of the library constituents. In this study, the implementation of such libraries on carbohydrate-lectin interactions was examined. The dynamic carbohydrate libraries were generated from a small set (four or six compounds) of initial carbohydrate dimers through mild disulfide interchange, and selection was performed under two conditions defining either adaptive or pre-equilibrated libraries. Upon initiation, libraries were formed that contained comparable amounts of 10 or 21 individual dimeric species, dynamically interchanging during the scrambling process. They were probed with respect to binding to the plant lectin concanavalin A, either present during library generation or added after equilibration. The libraries could be generated easily both in the presence and absence of the receptor, and a bis-mannose structure was preferentially bound and selected from the mixture. Scrambling of the library in the presence of the receptor resulted in slightly higher yields than when the receptor was added after scrambling, indicating that the receptor to some extent acts as a thermodynamic trap during library generation. The present results illustrate the extention of the DCC approach to carbohydrate recognition groups, the generation of isoenergetic dynamic libraries, and the implementation of either adaptive or pre-equilibrated procedures.

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Section: Introductionmentioning

confidence: 99%

In Situ Generation and Screening of a Dynamic Combinatorial Carbohydrate Library against Concanavalin A

2000

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“…Therefore, it becomes possible to switch both or any of the exchange equilibria on and off either by adding an oxidizing͞ reducing agent or by changing the pH of the solution. This is important for the application of the dynamic libraries in an evolutionary selection͞variation (22) or in the preequilibrated mode (25).…”

Section: Resultsmentioning

confidence: 99%

“…A number of such reactions have been tested, which include transacylation (12)(13)(14)(15), imine exchange (16)(17)(18)(19)(20), isomerization (21)(22)(23), thiol-disulfide exchange (24,25), and ligand exchange in coordination complexes (17,18,26).…”

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confidence: 99%

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Double-level “orthogonal” dynamic combinatorial libraries on transition metal template

Goral

Nelen²,

Елисеев³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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148

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Dynamic combinatorial libraries are mixtures of compounds that exist in a dynamic equilibrium and can be driven to compositional self adaptation via selective binding of a specific assembly of certain components to a molecular target. We present here an extension of this initial concept to dynamic libraries that consists of two levels, the first formed by the coordination of terpyridine-based ligands to the transition metal template, and the second, by the imine formation with the aldehyde substituents on the terpyridine moieties. Dialdehyde 7 has been synthesized, converted into a variety of ligands, oxime ethers L 11-L33 and acyl hydrazones L44-L77, and subsequently into corresponding cobalt complexes. A typical complex, Co(L 22)2 2؉ is shown to engage in rapid exchange with a competing ligand L11 and with another complex, Co(L22) 2 2؉ in 30% acetonitrile͞water at pH 7.0 and 25°C. The exchange in the corresponding Co(III) complexes is shown to be much slower. Imine exchange in the acyl hydrazone complexes (L 44-L77) is strongly controlled by pH and temperature. The two types of exchange, ligand and imine, can thus be used as independent equilibrium processes controlled by different types of external intervention, i.e., via oxidation͞reduction of the metal template and͞or change in the pH͞temperature of the medium. The resulting double-level dynamic libraries are therefore named orthogonal, in similarity with the orthogonal protecting groups in organic synthesis. Sample libraries of this type have been synthesized and showed the complete expected set of components in electrospray ionization MS. R apid development of combinatorial chemistry and highthroughput experimentation in basic and applied research (1-4) generates increasing demand in new approaches that simplify and expedite synthesis and screening of diverse arrays of compounds and materials. Dynamic combinatorial chemistry (5-11) has attracted increasing interest over recent years as a new approach that combines in one system the library generation and screening processes. The dynamic libraries are designed as mixtures of components that can reversibly interconvert in a dynamic equilibrium that is driven by molecular recognition of a specific molecular target toward that assembly or a subset of components that form the library constituent best bound to the target.One of the key issues in designing dynamic libraries is the choice of the reversible chemical reaction that can interconvert the library components. A number of such reactions have been tested, which include transacylation (12-15), imine exchange (16-20), isomerization (21-23), thiol-disulfide exchange (24, 25), and ligand exchange in coordination complexes (17,18,26).A logical development of dynamic combinatorial chemistry would aim toward the combination of two or more reversible processes within one library. To extend the comparison with ''static'' chemical libraries, such multilevel organization in the dynamic library would be similar to advancing from a static library of components having ...

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“…11 To address these problems numerous theoretical studies of DCLs have been done. [12][13][14][15][16] The studies suggested that, unless excessive amounts of molecular target are used, good binders have a high probability of being significantly amplified. However, a major limitation for application of DCC in drug discovery is the limited number of reversible covalent reactions appropriate to be used to synthesize DCLs.…”

Section: Dynamic Combinatorial Chemistry Methodsmentioning

confidence: 99%

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Maraković

Šinko

2017

ACSi

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Modern drug discovery is mainly based on the de novo synthesis of a large number of compounds with a diversity of chemical functionalities. Though the introduction of combinatorial chemistry enabled the preparation of large libraries of compounds from so-called building blocks, the problem of successfully identifying leads remains. The introduction of a dynamic combinatorial chemistry method served as a step forward due to the involvement of biological macromolecular targets (receptors) in the synthesis of high affinity products. The major breakthrough was a synthetic method in which building blocks are irreversibly combined due to the presence of a receptor. Here we present various receptor-based combinatorial chemistry approaches. Huisgen's cycloaddition (1,3-dipolar cycloaddition of azides and alkynes) forms stabile 1,2,3-triazoles with very high receptor affinity that can reach femtomolar levels, as the case with acetylcholinesterase inhibitors shows. Huisgen's cycloaddition can be applied to various receptors including acetylcholinesterase, acetylcholine binding protein, carbonic anhydrase-II, serine/threonine-protein kinase and minor groove of DNA.

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Use of Molecular Recognition To Drive Chemical Evolution: Mechanisms of an Automated Genetic Algorithm Implementation

Cited by 68 publications

References 62 publications

In Situ Generation and Screening of a Dynamic Combinatorial Carbohydrate Library against Concanavalin A

In Situ Generation and Screening of a Dynamic Combinatorial Carbohydrate Library against Concanavalin A

Double-level “orthogonal” dynamic combinatorial libraries on transition metal template

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

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