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Dynamic combinatorial chemistry

Sarah H Hewitt, Andrew J Wilson
Dynamic combinatorial chemistry (DCC) represents an approach, whereby traditional supramolecular scaffolds used for protein surface recognition might be exploited to achieve selective high affinity target recognition. Synthesis, in situ screening and amplification under selection pressure allows the generation of ligands, which bear different moieties capable of making multivalent non-covalent interactions with target proteins. Generic tetracarboxyphenyl porphyrin scaffolds bearing four hydrazide moieties have been used to form dynamic combinatorial libraries (DCLs) using aniline-catalyzed reversible hydrazone exchange reactions, in 10 % DMSO, 5 mm NH4 OAc, at pH 6...
April 30, 2018: European Journal of Organic Chemistry
Leticia Monjas, Lotteke J Y M Swier, Inda Setyawati, Dirk J Slotboom, Anna K H Hirsch
We applied dynamic combinatorial chemistry (DCC) to identify ligands of ThiT, the S-component of the energy-coupling factor (ECF) transporter for thiamine in Lactococcus lactis. We used a pre-equilibrated dynamic combinatorial library (DCL) and saturation-transfer difference (STD) NMR spectroscopy to identify ligands of ThiT. This is the first report in which DCC is used for fragment growing to an ill-defined pocket, and one of the first reports for its application with an integral membrane protein as target...
October 20, 2017: ChemMedChem
Yigit Altay, Meniz Tezcan, Sijbren Otto
Our knowledge regarding the early steps in the formation of evolvable life and what constitutes the minimal molecular basis of life remains far from complete. The recent emergence of systems chemistry reinvigorated the investigation of systems of self-replicating molecules to address these questions. Most of these studies focus on single replicators and the effects of replicators on the emergence of other replicators remains under-investigated. Here we show the cross-catalyzed emergence of a novel self-replicator from a dynamic combinatorial library made from a threonine containing peptide building block, which, by itself, only forms trimers and tetramers that do not replicate...
October 4, 2017: Journal of the American Chemical Society
Jian Fu, Huixiao Fu, Marc Dieu, Iman Halloum, Laurent Kremer, Yufen Xia, Weidong Pan, Stéphane P Vincent
In this study, we report a dynamic combinatorial approach along with highly efficient in situ screening to identify inhibitors of UDP-galactopyranose mutase (UGM), an essential enzyme involved in mycobacterial cell wall biosynthesis. These two technologies converged to the identification of a new UGM inhibitor chemotype. Importantly, the best molecule not only displayed high affinity for the target enzyme but also exhibited in vitro growth inhibition against whole Mycobacterium tuberculosis cells. The strategy described here provides an avenue to explore a novel inhibitor class for UGMs and paves the way for further pharmacological studies on tuberculosis treatment...
September 26, 2017: Chemical Communications: Chem Comm
Isaiah N Gober, Marcey L Waters
In the design of small molecule receptors for polar guests, much inspiration has been taken from proteins that have adapted effective ways to selectively bind polar molecules in aqueous environments. Nonetheless, molecular recognition of hydrophilic guests in water by synthetic receptors remains a challenging task. Here we report a new synthetic receptor, A2I, with improved affinity and selectivity for a biologically important polar guest, dimethyllysine (Kme2). A2I was prepared via redesign of a small molecule receptor (A2B) that preferentially binds trimethyllysine (Kme3) using dynamic combinatorial chemistry (DCC)...
September 26, 2017: Organic & Biomolecular Chemistry
Dennis Larsen, Anne Jeppesen, Claudia Kleinlein, Michael Pittelkow
Dynamic combinatorial libraries that equilibrate under thermodynamic control and can be trapped kinetically when desired are key to creating complex systems that can mimic dynamic biological systems, such as the biochemical system of life. A much-sought-after feature is the ability to turn off the dynamic exchange of the system, in order to investigate a transient state away from thermodynamic equilibrium, and then turn on the dynamic exchange again. We describe here the first use of thiosemicarbazone exchange to form dynamic combinatorial libraries...
August 3, 2017: Journal of Organic Chemistry
I R Sasselli, I P Moreira, R V Ulijn, T Tuttle
There is significant interest in the use of unmodified self-assembling peptides as building blocks for functional, supramolecular biomaterials. Recently, dynamic peptide libraries (DPLs) have been proposed to select self-assembling materials from dynamically exchanging mixtures of dipeptide inputs in the presence of a nonspecific protease enzyme, where peptide sequences are selected and amplified based on their self-assembling tendencies. It was shown that the results of the DPL of mixed sequences (e.g. starting from a mixture of dileucine, L2 , and diphenylalanine, F2 ) did not give the same outcome as the separate L2 and F2 libraries (which give rise to the formation of F6 and L6 ), implying that interactions between these sequences could disrupt the self-assembly...
August 9, 2017: Organic & Biomolecular Chemistry
Priska Frei, Lijuan Pang, Marleen Silbermann, Deniz Eriş, Tobias Mühlethaler, Oliver Schwardt, Beat Ernst
Target-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors of pharmacologically relevant targets. In this contribution, we present an application for a bacterial target, the lectin FimH, a crucial virulence factor of uropathogenic E. coli being the main cause of urinary tract infections. A small dynamic library of acylhydrazones was formed from aldehydes and hydrazides and equilibrated at neutral pH in presence of aniline as nucleophilic catalyst...
August 25, 2017: Chemistry: a European Journal
Jean Septavaux, Geoffroy Germain, Julien Leclaire
Extraction and purification of basic chemicals from complex mixtures has been a persistent issue throughout the development of the chemical sciences. The chemical industry and academic research have grown over the centuries by following a deconstruction-reconstruction approach, reminiscent of the metabolism process. Chemists have designed and optimized extraction, purification, and transformation processes of molecules from natural deposits (fossil fuels, biomass, ores), in order to reassemble them into complex adducts...
June 23, 2017: Accounts of Chemical Research
Dominik K Kölmel, Eric T Kool
The formation of oximes and hydrazones is employed in numerous scientific fields as a simple and versatile conjugation strategy. This imine-forming reaction is applied in fields as diverse as polymer chemistry, biomaterials and hydrogels, dynamic combinatorial chemistry, organic synthesis, and chemical biology. Here we outline chemical developments in this field, with special focus on the past ∼10 years of developments. Recent strategies for installing reactive carbonyl groups and α-nucleophiles into biomolecules are described...
August 9, 2017: Chemical Reviews
Angel M Valdivielso, Francesc Puig-Castellví, Joan Atcher, Jordi Solà, Romà Tauler, Ignacio Alfonso
Dynamic combinatorial libraries (DCLs) are excellent benchmark models to study the stimuli-responsiveness of chemical networks. However, increasingly complex systems are difficult to analyze with simple data analysis methods, because many variables and connections must be considered for their full understanding. Here we propose the use of multivariate data analysis methods to bisect the evolution of a complex synthetic dynamic library of pseudopeptidic macrocycles, containing side chains with charges of different sign...
August 10, 2017: Chemistry: a European Journal
Brendan C Peacor, Christopher M Ramsay, Marcey L Waters
Post-translational modifications (PTMs) on histone tails act in diverse combinations in the 'histone code' to control gene expression, with dysregulation observed in a variety of diseases. However, detection and sensing methods are limited, expensive, and/or low-throughput, including MS and antibody based detection. We found that by combining four synthetic receptors developed by dynamic combinatorial chemistry (DCC) in an indicator displacement system, we are able to create a pattern-based sensor platform that can discriminate single PTMs such as methylation and acetylation on a representative histone peptide with 100% accuracy as well as peptides bearing both dimethyl and trimethyl lysine in the presence of arginine methylation, which has not previously been demonstrated, and can even correctly distinguish the position of lysine methylation individually or in the presence of other PTMs...
February 1, 2017: Chemical Science
Bartosz M Matysiak, Piotr Nowak, Ivica Cvrtila, Charalampos G Pappas, Bin Liu, Dávid Komáromy, Sijbren Otto
The ability to design reaction networks with high, but addressable complexity is a necessary prerequisite to make advanced functional chemical systems. Dynamic combinatorial chemistry has proven to be a useful tool in achieving complexity, however with some limitations in controlling it. Herein we introduce the concept of antiparallel chemistries, in which the same functional group can be channeled into one of two reversible chemistries depending on a controllable parameter. Such systems allow both for achieving complexity, by combinatorial chemistry, and addressing it, by switching from one chemistry to another by controlling an external parameter...
May 17, 2017: Journal of the American Chemical Society
Nikola Maraković, Goran Šinko
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...
2017: Acta Chimica Slovenica
Jalal Soubhye, Michel Gelbcke, Pierre Van Antwerpen, François Dufrasne, Mokhtaria Yasmina Boufadi, Jean Nève, Paul G Furtmüller, Christian Obinger, Karim Zouaoui Boudjeltia, Franck Meyer
The implementation of dynamic combinatorial libraries allowed the determination of highly active reversible and irreversible inhibitors of myeloperoxidase (MPO) at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. Finally, in vivo evaluation showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation.
February 9, 2017: ACS Medicinal Chemistry Letters
Zeynep Kanlidere, Oleg Jochim, Marta Cal, Ulf Diederichsen
Dynamic combinatorial chemistry (DCC) is an attractive method to efficiently generate libraries of molecules from simpler building blocks by reversible reactions under thermodynamic control. Here we focus on the chemical modification of DNA oligonucleotides with acyclic diol linkers and demonstrate their potential for the deoxyribonucleic acid functionalization and generation of libraries of reversibly interconverting building blocks. The syntheses of phosphoramidite building blocks derived from D-threoninol are presented in two variants with protected amino or thiol groups...
2016: Beilstein Journal of Organic Chemistry
Helen M Seifert, Karina Ramirez Trejo, Eric V Anslyn
Dynamic covalent reactions are widely used in dynamic combinatorial chemistry. Most of these reactions are run under differing reaction conditions and exhibit cross-reactivity when components of multiple reactions are present in one reaction vessel. Herein, we report the study of four dynamic covalent reactions that react reversibly under identical reaction conditions and do not exhibit any cross-reactivity. Dynamic behavior was shown via (1)H NMR based exchange experiments. Computational deconvolution of (1)H NMR spectra containing the components for more than one of the orthogonal reactions allowed for a semiquantitative analysis of the complex mixtures formed, showing that the reactions proceed independently of each other...
August 31, 2016: Journal of the American Chemical Society
Renjie Huang, Ivanhoe K H Leung
Protein-directed dynamic combinatorial chemistry is an emerging technique for efficient discovery of novel chemical structures for binding to a target protein. Typically, this method relies on a library of small molecules that react reversibly with each other to generate a combinatorial library. The components in the combinatorial library are at equilibrium with each other under thermodynamic control. When a protein is added to the equilibrium mixture, and if the protein interacts with any components of the combinatorial library, the position of the equilibrium will shift and those components that interact with the protein will be amplified, which can then be identified by a suitable biophysical technique...
July 16, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Milon Mondal, Nedyalka Radeva, Hugo Fanlo-Virgós, Sijbren Otto, Gerhard Klebe, Anna K H Hirsch
Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors...
August 1, 2016: Angewandte Chemie
Ping Gao, Lin Sun, Junsu Zhou, Xiao Li, Peng Zhan, Xinyong Liu
INTRODUCTION: In recent years, a variety of new synthetic methodologies and concepts have been proposed in the search for new pharmaceutical lead structures and optimization. Notably, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry approach has drawn great attention and has become a powerful tool for the generation of privileged medicinal skeletons in the discovery of anti-HIV agents. This is due to the high degree of reliability, complete specificity (chemoselectivity and regioselectivity), mild conditions, and the biocompatibility of the reactants...
September 2016: Expert Opinion on Drug Discovery
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