Exploring Drug Target Flexibility Using <i>in Situ</i> Click Chemistry: Application to a Mycobacterial Transcriptional Regulator

Willand, Nicolas; Desroses, Matthieu; Toto, Patrick; Dirié, Bertrand; Lens, Zoé; Villeret, Vincent; Rucktooa, Prakash; Locht, Camille; Baulard, Alain R.; Déprez, Benoît

doi:10.1021/cb100177g

Cited by 61 publications

(83 citation statements)

References 33 publications

(38 reference statements)

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“…These structures have been critical in the design of synthetic EthR ligands (see below), and subsequent structures of EthR have been solved in complex with a number of these molecules (63)(64)(65). In one study, two related analogs were found to bind EthR with different orientations, supporting the extremely plastic nature of the EthR ligand-binding pocket (63).…”

Section: Tfr-ligand Interactionsmentioning

confidence: 98%

The TetR Family of Regulators

Cuthbertson

Nodwell

2013

Microbiol Mol Biol Rev

467

512

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SUMMARY The most common prokaryotic signal transduction mechanisms are the one-component systems in which a single polypeptide contains both a sensory domain and a DNA-binding domain. Among the >20 classes of one-component systems, the TetR family of regulators (TFRs) are widely associated with antibiotic resistance and the regulation of genes encoding small-molecule exporters. However, TFRs play a much broader role, controlling genes involved in metabolism, antibiotic production, quorum sensing, and many other aspects of prokaryotic physiology. There are several well-established model systems for understanding these important proteins, and structural studies have begun to unveil the mechanisms by which they bind DNA and recognize small-molecule ligands. The sequences for more than 200,000 TFRs are available in the public databases, and genomics studies are identifying their target genes. Three-dimensional structures have been solved for close to 200 TFRs. Comparison of these structures reveals a common overall architecture of nine conserved α helices. The most important open question concerning TFR biology is the nature and diversity of their ligands and how these relate to the biochemical processes under their control.

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Section: Tfr-ligand Interactionsmentioning

confidence: 98%

The TetR Family of Regulators

Cuthbertson

Nodwell

2013

Microbiol Mol Biol Rev

467

512

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“…The in situ formed inhibitor, displayed 10-fold higher activity than the starting azide, and induced a significant conformational change of the ligand-binding domain of EthR. 145 …”

Section: Dna Minor Groove Templation Rolementioning

confidence: 98%

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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“…ase, [14][15][16][17] carbonic anhydrase, [18][19][20][21] human immunodeficiency virus (HIV)-1 protease, 22) Serratia marcescens chitinase (SmChi), [23][24][25] Mycobacterium tuberculosis EthR protein, 26) Akt1, 27) acetylcholine binding protein, 28) G-Quadruplex 29) and biotin protein ligase inhibitors 30) have served as templates. Here, we report in situ click chemistry approaches, focusing on hDAO as the target enzyme to generate novel hDAO inhibitors.…”

Section: This Article Is Dedicated To Professor Satoshi ōMura In Celementioning

confidence: 99%

<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

Toguchi

Hirose

Yorita

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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In situ click chemistry is a target-guided synthesis approach for discovering novel lead compounds by assembling organic azides and alkynes into triazoles inside the affinity site of target biogenic molecules such as proteins. We report in situ click chemistry screening with human D-amino acid oxidase (hDAO), which led to the identification of a more potent hDAO inhibitor. The hDAO inhibitors have chemotherapeutic potential as antipsychotic agents. The new inhibitor displayed competitive inhibition of hDAO and showed significantly increased inhibitory activity against hDAO compared with that of an anchor molecule of in situ click chemistry.Key words fragment-based lead discovery; templated reaction; ligand-binding site; drug discovery; triazole formation; ligand affinity Although D-amino acids exist in a wide range of organisms, they are nonetheless often called unnatural amino acids. D-Serine is abundant in the forebrain and acts as an endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptors to enhance neurotransmission. 1) D-Amino acid oxidase (DAO) was the first flavoenzyme to be identified, in 1935 by Krebs,2) and catalyzes the oxidative deamination reaction of D-amino acids. This reaction by human DAO (hDAO) in the brain primarily converts D-serine to hydroxypyruvate to regulate the concentration of D-serine. The overexpression of hDAO in the brain therefore causes neuropsychiatric disorders such as schizophrenia, a serious public health problem that affects nearly 0.8% of the global population, by reducing the amount of D-serine below the level required for adequate neuronal function.3,4) Furthermore, a protein from the human gene G72 has been identified as an interacting partner to activate hDAO, and the association of both DAO and gene G72 with schizophrenia together with activation of hDAO activity by a G72 protein product points to the involvement of the regulation of NMDA receptor. 5) Thus, hDAO inhibitors have potential to be lead compounds to the development of therapeutic agents for schizophrenia.Within the realm of click chemistry research, triazole formation between organic azide and alkyne is widely recognized. Triazole formation includes the 1,3-dipolar reaction known as the Huisgen cycloaddition, [6][7][8][9] and catalytic reactions that selectively afford the corresponding 1,4-substituted triazole or 1,5-substituted triazole using monovalent copper 10,11) or ruthenium reagents, 12,13) respectively. In situ click chemistry is a target-guided synthesis (TGS) method for the fast and efficient production of potential inhibitors against target biomolecules such as enzymes. Using this approach, complementary alkyne and azide building are assembled at binding sites and then accelerate the Huisgen 1,3-dipolar cycloaddition reaction to afford the corresponding conventional triazole, as illustrated in Fig. 1.To date, in situ click chemistry research has garnered success in inhibitor explorations where acetylcholinester-

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Exploring Drug Target Flexibility Using in Situ Click Chemistry: Application to a Mycobacterial Transcriptional Regulator

Cited by 61 publications

References 33 publications

The TetR Family of Regulators

The TetR Family of Regulators

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

<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

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