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Catalytic Self-Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library
KTH, Tidigare Institutioner, Kemi.
KTH, Tidigare Institutioner, Kemi.
KTH, Tidigare Institutioner, Kemi.ORCID-id: 0000-0002-1533-6514
2004 (Engelska)Ingår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 43, nr 28, s. 3716-3718Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2004. Vol. 43, nr 28, s. 3716-3718
Nyckelord [en]
combinatorial chemistry; enzyme catalysis hydrolysis; proteomics; transesterification
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:kth:diva-8265DOI: 10.1002/anie.200454165ISI: 000222793600019PubMedID: 15248281Scopus ID: 2-s2.0-4544244707OAI: oai:DiVA.org:kth-8265DiVA, id: diva2:13542
Anmärkning
QC 20100818Tillgänglig från: 2008-04-25 Skapad: 2008-04-25 Senast uppdaterad: 2020-03-09Bibliografiskt granskad
Ingår i avhandling
1. Dynamic Systems for Screening, Control and Identification of Protein-Ligand Interactions
Öppna denna publikation i ny flik eller fönster >>Dynamic Systems for Screening, Control and Identification of Protein-Ligand Interactions
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: KTH, 2008. s. 64
Serie
TRITA-CHE-Report, ISSN 1654-1081 ; 2008:31
Nyckelord
Dynamic combinatorial chemistry, Dynamic kinetic/combinatorial resolution, Catalytic screening, Transthiolesterification, Thiol/disulfide interchange, Nitroaldol reaction, Lectins, Hydrolases, Dynamic self-inhibition
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:kth:diva-4709 (URN)978-91-7178-944-0 (ISBN)
Disputation
2008-05-09, F3, Lindstedtsvägen 26, Stockholm, 13:00
Opponent
Handledare
Anmärkning

QC 20100818

Tillgänglig från: 2008-04-25 Skapad: 2008-04-25 Senast uppdaterad: 2017-02-23Bibliografiskt granskad
2. Reversible Sulfur Reactions in Pre-Equilibrated and Catalytic Self-Screening Dynamic Combinatorial Chemistry Protocols
Öppna denna publikation i ny flik eller fönster >>Reversible Sulfur Reactions in Pre-Equilibrated and Catalytic Self-Screening Dynamic Combinatorial Chemistry Protocols
2006 (Engelska)Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Dynamic Combinatorial Chemistry (DCC) is a recently introduced supramolecular 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 date, only a handful of different systems and formats have been used. Hence, 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 reversible sulfur reactions, thiol/disulfide interchange and transthiolesterification (the latter being a new reaction type for DCC), 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. Furthermore, two new screening/analysis methods not previously used in DCC are also presented; the quartz crystal microbalance (QCM)-technique and catalytic self-screening.

Ort, förlag, år, upplaga, sidor
Stockholm: KTH, 2006. s. 44
Serie
Trita-IOK, ISSN 1100-7974 ; 2006:102
Nyckelord
Dynamic Combinatorial Chemistry, Reversible sulfur reactions, Catalytic self-screening, Carbohydrates, Lectins, Quartz Crystal Microbalance
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:kth:diva-3917 (URN)91-7178-323-7 (ISBN)
Presentation
2006-05-02, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00
Anmärkning
QC 20101118Tillgänglig från: 2006-04-10 Skapad: 2006-04-10 Senast uppdaterad: 2010-11-18Bibliografiskt granskad

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