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Dynamic Systems for Screening, Control and Identification of Protein-Ligand Interactions
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
2008 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Dynamic systems for screening, control and identification of different protein-ligand interactions are presented. Dynamic chemistry is used to produce new compounds/constituents in situ that can interact with a target molecule. Several entities can be introduced at the same time and interact with one another. These molecules make a dynamic combinatorial library (DCL) which is used in dynamic combinatorial chemistry (DCC). DCC is a recently introduced approach to generate dynamically interchanging libraries of compounds. These libraries are made of different building blocks that reversibly interact with one another and spontaneously assemble to encompass all possible combinations. If a target molecule, for instance a receptor is added to the system and one or more molecules show affinity to the target species, these compounds will, according to Le Châtelier´s principle, be amplified on the expense of the other non-bonding constituents. To further advance the technique, especially when biological systems are targeted, new reaction types and new screening methods are necessary. This thesis describes the development of different reversible reactions, thiol/disulfide interchange, transthiolesterification and the nitroaldol (Henry) reaction as means of generating reversible covalent bond reactions. Two different types of target proteins are used, enzymes belonging to the hydrolase family and the plant lectin Concanavalin A.

Dynamic combinatorial resolution (DCR) is presented. This new concept relies on the consecutive kinetic resolution of dynamic combinatorial libraries, leading to complete amplification and control of dynamically interchangeable processes. By applying a kinetically controlled step to a thermodynamically controlled system, complete transformation and amplification can be obtained. The concept has been demonstrated by developing transthiolesterification and nitroaldol exchange reactions to generate diversity, forming libraries under thermodynamic control, and used in one-pot processes with kinetically controlled enzyme-mediated resolution. The results demonstrate that the reaction types are useful for the generation of dynamic libraries, and that the dynamic combinatorial resolution concept is highly valuable for efficient substrate identification, asymmetric synthesis, and library screening.

The thesis also describes three other dynamic chemistry protocols. The first one describes dynamic kinetic resolution (DKR) of nitroaldol adducts by combined lipase catalysis. The second one describes finding lectin inhibitors from a glycodisulfide library and the third one describes finding an inhibitor of acetylcholinesterase using a tandem driven dynamic self-inhibition approach.

Place, publisher, year, edition, pages
Stockholm: KTH , 2008. , 64 p.
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2008:31
Keyword [en]
Dynamic combinatorial chemistry, Dynamic kinetic/combinatorial resolution, Catalytic screening, Transthiolesterification, Thiol/disulfide interchange, Nitroaldol reaction, Lectins, Hydrolases, Dynamic self-inhibition
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-4709ISBN: 978-91-7178-944-0 OAI: oai:DiVA.org:kth-4709DiVA: diva2:13547
Public defence
2008-05-09, F3, Lindstedtsvägen 26, Stockholm, 13:00
Opponent
Supervisors
Note

QC 20100818

Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-02-23Bibliographically approved
List of papers
1. Direct Asymmetric Dynamic Kinetic Resolution by Combined Lipase Catalysis and Nitroaldol (Henry) Reaction
Open this publication in new window or tab >>Direct Asymmetric Dynamic Kinetic Resolution by Combined Lipase Catalysis and Nitroaldol (Henry) Reaction
2008 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 350, no 3, 448-452 p.Article in journal (Refereed) Published
Abstract [en]

The asymmetric synthesis of β-nitroalkanol derivatives was simply achieved by a combined nitroaldol (Henry) reaction with lipase-catalyzed transesterification in high yield and enantiomeric purity (up to 92% and 99% ee) through a direct one-pot procedure.

Keyword
Dynamic kinetic resolution; Enzyme catalysis; Nitroaldol (Henry) reaction; Secondary alcohols
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-8264 (URN)10.1002/adsc.200700432 (DOI)000253600600018 ()2-s2.0-49049106632 (Scopus ID)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
2. Catalytic Self-Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library
Open this publication in new window or tab >>Catalytic Self-Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library
2004 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 43, no 28, 3716-3718 p.Article in journal (Refereed) Published
Abstract [en]

Simply the best: Dynamic combinatorial chemistry coupled to enzyme catalysis was used to identify enzyme substrates in a library constructed from a series of thioesters and thiols by transesterification. The library was directly coupled to the catalytic action of acetylcholinesterase, which selectively hydrolyzed the best substrate candidates (see schematic representation). The process allowed rapid identification of discrete substrates.

Keyword
combinatorial chemistry; enzyme catalysis hydrolysis; proteomics; transesterification
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-8265 (URN)10.1002/anie.200454165 (DOI)000222793600019 ()2-s2.0-4544244707 (Scopus ID)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
3. Dynamic Combinatorial Thiolester Libraries for Efficient Catalytic Self-Screening of Hydrolase Substrates
Open this publication in new window or tab >>Dynamic Combinatorial Thiolester Libraries for Efficient Catalytic Self-Screening of Hydrolase Substrates
2006 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 1, 285-291 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic combinatorial thiolester libraries were efficiently generated from pools of thiols and acyl functionalities through reversible transthiolesterification in aqueous media at neutral pH. The dynamic features of the library generation were investigated, and the libraries were screened against acetylcholinesterase, clearly demonstrating the catalytic self-screening of its substrates from the constituents. Acetyl- and propionylthiocholine were easily identified as the best substrates for the enzyme, whereas other constituents showed lower efficiency or were inactive. A range of hydrolases was furthermore screened for rapid substrate identification, clearly demonstrating the differences in selectivity. The results show that transthiolesterification is a useful method to generate dynamic libraries, and that the catalytic self -screening concept is highly valuable for substrate identification.

Keyword
combinatorial chemistry; enzyrne catalysis; hydrolysis; transesterification
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-8266 (URN)10.1002/ejoc.200500699 (DOI)000234237500028 ()2-s2.0-33745819380 (Scopus ID)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
4. Dynamic Combinatorial Resolution: Direct Asymmetric Lipase-Mediated Screening of a Dynamic Nitroaldol Library
Open this publication in new window or tab >>Dynamic Combinatorial Resolution: Direct Asymmetric Lipase-Mediated Screening of a Dynamic Nitroaldol Library
2007 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 46, no 6, 948-950 p.Article in journal (Refereed) Published
Abstract [en]

(Chemical Equation Presented) A disturbance in the library: The nitroaldol (Henry) reaction was developed as an efficient C-C bond-forming route to dynamic combinatorial libraries (DCLs). These DCLs generated under thermodynamic control were coupled in a one-pot process with kinetically controlled lipase-mediated transesterification (see scheme). The asymmetric resolution of the DCLs by the enzyme led to enantiomerically pure β-nitroacetates in high yield.

Keyword
Aldol reaction; Combinatorial chemistry; Dynamic chemistry; Enzyme catalysis; Reversible reactions
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-8267 (URN)10.1002/anie.200603740 (DOI)000244146500026 ()2-s2.0-33846687723 (Scopus ID)
Note
QC 20100506Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
5. Tandem Driven Dynamic Self-Inhibition of Acetylcholinesterase
Open this publication in new window or tab >>Tandem Driven Dynamic Self-Inhibition of Acetylcholinesterase
(English)Manuscript (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-8268 (URN)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2010-08-18Bibliographically approved
6. Quartz crystal microbalance bioaffinity sensor for rapid identification of glycosyldisulfide lectin inhibitors from a dynamic combinatorial library
Open this publication in new window or tab >>Quartz crystal microbalance bioaffinity sensor for rapid identification of glycosyldisulfide lectin inhibitors from a dynamic combinatorial library
Show others...
2006 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 22, no 1, 42-48 p.Article in journal (Refereed) Published
Abstract [en]

Carbohydrate-lectin,interactions were probed with dynamic combinatorial libraries, using the plant lectin Concanavalin A as target species. The dynamic combinatorial libraries were generated from a pool of thiol components through reversible thiol-disulfide interchange, and screened using a simple and efficient method based on a quartz crystal microbalance setup. It was found that dimers based on 1-thio- and 6-thin-mannose analogues were the most active inhibitors. Furthermore, the results clearly show that the 6-thio-mannose possess unique characteristics compared to its oxygen-containing counterpart.

Keyword
quartz crystal microbalance; dynamic combinatorial chemistry; glycochemistry; carbohydrates; lectins; molecular recognition
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-8269 (URN)10.1016/j.bios.2005.11.024 (DOI)000241040600006 ()2-s2.0-33746607715 (Scopus ID)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved

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