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Book: Chemogenomics

Merk, Daniel / Chaikuad, Apirat

methods and protocols

(Methods in molecular biology ; 2706 ; Springer protocols)

2023

Author's details	edited by Daniel Merk, Apirat Chaikuad
Series title	Methods in molecular biology ; 2706 Springer protocols
Collection
Keywords	Chemogenomics
Subject code	615.19
Language	English
Size	xi, 234 Seiten, Illustrationen
Publisher	Humana Press
Publishing place	New York, NY
Publishing country	United States
Document type	Book
HBZ-ID	HT030343793
ISBN	9781071633960 ; 9781071633977 ; 1071633961 ; 107163397X
Database	Catalogue ZB MED Medicine, Health

In stock of ZB MED Cologne/Königswinter

Shelf mark	Loan status	Location
Zs A 7042 -2706-	not available for loan	Lesesaal EG

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Article ; Online: An Introduction to Chemogenomics.

Chaikuad, Apirat / Merk, Daniel

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2706, Page(s) 1–10

Abstract: Chemogenomics is an innovative approach in chemical biology that synergizes combinatorial chemistry and genomic and proteomic biology to systematically study the response of a biological system to a set of compounds, which can aid the identification and ... ...

Abstract	Chemogenomics is an innovative approach in chemical biology that synergizes combinatorial chemistry and genomic and proteomic biology to systematically study the response of a biological system to a set of compounds, which can aid the identification and validation of biological targets as well as biologically active small-molecule agents responsible for a phenotypic outcome. Central to this strategy is a collection of chemically diverse compounds, a so-called chemogenomics library. Selection and annotation of vastly available chemogenomic compound candidates for an inclusion in such set present a challenge, but optimal compound selection is critical for success of chemogenomics. The library can be used in a wide variety of research applications from biological mechanism deconvolution to drug discovery. However, phenotypic screening methods are typically required to be high-throughput and equipped with a systematic analysis of complex biological-chemical interactions. This chapter provides a general outline to the chemogenomics approach, including concept and critical steps in all stages of this innovative chemical biology strategy.
MeSH term(s)	Drug Design ; Proteomics ; Genomics/methods ; Drug Discovery/methods
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3397-7_1
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Assessing reversible and irreversible binding effects of kinase covalent inhibitors through ADP-Glo assays.

Schröder, Martin / Chaikuad, Apirat

STAR protocols

2021 Volume 2, Issue 3, Page(s) 100717

Abstract: Typical enzymatic inhibition assays often demonstrate improved potency for kinase covalent inhibitors compared to reversible inhibitors. This can primarily be attributed to the irreversible mode of action and could affect the evaluations of the ATP- ... ...

Abstract	Typical enzymatic inhibition assays often demonstrate improved potency for kinase covalent inhibitors compared to reversible inhibitors. This can primarily be attributed to the irreversible mode of action and could affect the evaluations of the ATP-competitive nature of covalent inhibitors, hindering optimization of these compounds. Here, we describe a version of ADP-Glo assay, in which modification of inhibitor incubation time in the presence or absence of ATP enables a quick assessment of relative reversible and irreversible effects of kinase covalent inhibitors. For complete details on the use and execution of this protocol, please refer to Schröder et al. (2020).
MeSH term(s)	Adenosine Diphosphate/analysis ; Adenosine Diphosphate/chemistry ; Drug Discovery/methods ; Luminescent Measurements/methods ; Phosphotransferases/analysis ; Protein Kinase Inhibitors/chemistry
Chemical Substances	Protein Kinase Inhibitors ; Adenosine Diphosphate (61D2G4IYVH) ; Phosphotransferases (EC 2.7.-)
Language	English
Publishing date	2021-08-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2021.100717
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Structural insights into a regulatory mechanism of FIR RRM1-FUSE interaction.

Ni, Xiaomin / Joerger, Andreas C / Chaikuad, Apirat / Knapp, Stefan

Open biology

2023 Volume 13, Issue 5, Page(s) 230031

Abstract: FUBP-interacting repressor (FIR) is a suppressor of transcription of the proto-oncogene MYC. FIR binds to the far upstream element (FUSE) of the MYC promoter. Competition of FIR with FUSE-binding protein 1 (FUBP1) is a key mechanism of MYC ... ...

Abstract	FUBP-interacting repressor (FIR) is a suppressor of transcription of the proto-oncogene MYC. FIR binds to the far upstream element (FUSE) of the MYC promoter. Competition of FIR with FUSE-binding protein 1 (FUBP1) is a key mechanism of MYC transcriptional regulation. To gain insights into the structural mechanisms regulating FIR DNA interaction, we determined the crystal structure of two FIR RRM domains (RRM1-2) with single-stranded FUSE DNA sequences. These structures revealed an ability of the RRM domain to recognize diverse FUSE regions through distinct intermolecular interactions and binding modes. Comparative structural analyses against available RRM-ssDNA/RNA complexes showed that the nucleotide configurations in FIR were similar to those in other RRMs that harbour a tyrosine at the conserved aromatic position in the RNP2 motif (Y-type RRM), but not those with a phenylalanine (F-type RRM). Site-directed mutagenesis experiments demonstrated that a single substitution, Y115F, altered the binding affinities of oligonucleotides to FIR RRM, suggesting an important role of this conserved aromatic residue in ssDNA/RNA interactions. Our study provides the structural basis for further mechanistic studies on this important protein-DNA interaction.
MeSH term(s)	RNA Splicing Factors ; Repressor Proteins/metabolism ; Protein Binding ; RNA/metabolism ; DNA/metabolism
Chemical Substances	RNA Splicing Factors ; Repressor Proteins ; RNA (63231-63-0) ; DNA (9007-49-2)
Language	English
Publishing date	2023-05-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2630944-0
ISSN	2046-2441 ; 2046-2441
ISSN (online)	2046-2441
ISSN	2046-2441
DOI	10.1098/rsob.230031
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Comparative structural analyses of the NHL domains from the human E3 ligase TRIM-NHL family.

Chaikuad, Apirat / Zhubi, Rezart / Tredup, Claudia / Knapp, Stefan

IUCrJ

2022 Volume 9, Issue Pt 6, Page(s) 720–727

Abstract: Tripartite motif (TRIM) proteins constitute one of the largest subfamilies of the RING-type E3 ubiquitin ligases that play a role in diverse processes from homeostasis and immune response to viral restriction. While TRIM proteins typically harbor an N- ... ...

Abstract	Tripartite motif (TRIM) proteins constitute one of the largest subfamilies of the RING-type E3 ubiquitin ligases that play a role in diverse processes from homeostasis and immune response to viral restriction. While TRIM proteins typically harbor an N-terminal RING finger, a B-box and a coiled-coil domain, a high degree of diversity lies in their C termini that contain diverse protein interaction modules, most of which, both structures and their roles in intermolecular interactions, remain unknown. Here, high-resolution crystal structures of the NHL domains of three of the four human TRIM-NHL proteins, namely TRIM2, TRIM3 and TRIM71, are presented. Comparative structural analyses revealed that, despite sharing an evolutionarily conserved six-bladed β-propeller architecture, the low sequence identities resulted in distinct properties of these interaction domains at their putative binding sites for macromolecules. Interestingly, residues lining the binding cavities represent a hotspot for genetic mutations linked to several diseases. Thus, high sequence diversity within the conserved NHL domains might be essential for differentiating binding partners among TRIM-NHL proteins.
Language	English
Publishing date	2022-09-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2754953-7
ISSN	2052-2525
ISSN	2052-2525
DOI	10.1107/S2052252522008582
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A Consensus Compound/Bioactivity Dataset for Data-Driven Drug Design and Chemogenomics.

Isigkeit, Laura / Chaikuad, Apirat / Merk, Daniel

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 8

Abstract: Publicly available compound and bioactivity databases provide an essential basis for data-driven applications in life-science research and drug design. By analyzing several bioactivity repositories, we discovered differences in compound and target ... ...

Abstract	Publicly available compound and bioactivity databases provide an essential basis for data-driven applications in life-science research and drug design. By analyzing several bioactivity repositories, we discovered differences in compound and target coverage advocating the combined use of data from multiple sources. Using data from ChEMBL, PubChem, IUPHAR/BPS, BindingDB, and Probes & Drugs, we assembled a consensus dataset focusing on small molecules with bioactivity on human macromolecular targets. This allowed an improved coverage of compound space and targets, and an automated comparison and curation of structural and bioactivity data to reveal potentially erroneous entries and increase confidence. The consensus dataset comprised of more than 1.1 million compounds with over 10.9 million bioactivity data points with annotations on assay type and bioactivity confidence, providing a useful ensemble for computational applications in drug design and chemogenomics.
MeSH term(s)	Consensus ; Databases, Factual ; Drug Design ; Humans
Language	English
Publishing date	2022-04-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27082513
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Article: Mutation in the Common Docking Domain Affects MAP Kinase ERK2 Catalysis and Stability.

Novak, Leonore / Petrosino, Maria / Pasquo, Alessandra / Chaikuad, Apirat / Chiaraluce, Roberta / Knapp, Stefan / Consalvi, Valerio

Cancers

2023 Volume 15, Issue 11

Abstract: The extracellular-signal-regulated kinase 2 (ERK2), a mitogen-activated protein kinase (MAPK) located downstream of the Ras-Raf-MEK-ERK signal transduction cascade, is involved in the regulation of a large variety of cellular processes. The ERK2, ... ...

Abstract	The extracellular-signal-regulated kinase 2 (ERK2), a mitogen-activated protein kinase (MAPK) located downstream of the Ras-Raf-MEK-ERK signal transduction cascade, is involved in the regulation of a large variety of cellular processes. The ERK2, activated by phosphorylation, is the principal effector of a central signaling cascade that converts extracellular stimuli into cells. Deregulation of the ERK2 signaling pathway is related to many human diseases, including cancer. This study reports a comprehensive biophysical analysis of structural, function, and stability data of pure, recombinant human non-phosphorylated (NP-) and phosphorylated (P-) ERK2 wild-type and missense variants in the common docking site (CD-site) found in cancer tissues. Because the CD-site is involved in interaction with protein substrates and regulators, a biophysical characterization of missense variants adds information about the impact of point mutations on the ERK2 structure-function relationship. Most of the P-ERK2 variants in the CD-site display a reduced catalytic efficiency, and for the P-ERK2 D321E, D321N, D321V and E322K, changes in thermodynamic stability are observed. The thermal stability of NP-ERK2 and P-ERK2 D321E, D321G, and E322K is decreased with respect to the wild-type. In general, a single residue mutation in the CD-site may lead to structural local changes that reflects in alterations in the global ERK2 stability and catalysis.
Language	English
Publishing date	2023-05-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15112938
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Comparative structural analyses and nucleotide-binding characterization of the four KH domains of FUBP1.

Ni, Xiaomin / Knapp, Stefan / Chaikuad, Apirat

Scientific reports

2020 Volume 10, Issue 1, Page(s) 13459

Abstract: The FUBP1-FUSE complex is an essential component of a transcription molecular machinery that is necessary for tight regulation of expression of many key genes including c-Myc and p21. FUBP1 utilizes its four articulated KH modules, which function ... ...

Abstract	The FUBP1-FUSE complex is an essential component of a transcription molecular machinery that is necessary for tight regulation of expression of many key genes including c-Myc and p21. FUBP1 utilizes its four articulated KH modules, which function cooperatively, for FUSE nucleotide binding. To understand molecular mechanisms fundamental to the intermolecular interaction, we present a set of crystal structures, as well ssDNA-binding characterization of FUBP1 KH domains. All KH1-4 motifs were highly topologically conserved, and were able to interact with FUSE individually and independently. Nevertheless, differences in nucleotide binding properties among the four KH domains were evident, including higher nucleotide-binding potency for KH3 as well as diverse nucleotide sequence preferences. Variations in amino acid compositions at one side of the binding cleft responsible for nucleobase resulted in diverse shapes and electrostatic charge interaction, which might feasibly be a contributing factor for different nucleotide-binding propensities among KH1-4. Nonetheless, conservation of structure and nucleotide-binding property in all four KH motifs is essential for the cooperativity of multi KH modules present in FUBP1 towards nanomolar affinity for FUSE interaction. Comprehensive structural comparison and ssDNA binding characteristics of all four KH domains presented here provide molecular insights at a fundamental level that might be beneficial for elucidating the mechanisms of the FUBP1-FUSE interaction.
MeSH term(s)	Amino Acid Sequence/genetics ; Base Sequence/genetics ; Crystallography, X-Ray/methods ; DNA Helicases/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Humans ; Models, Molecular ; Nucleotides/metabolism ; Protein Binding/genetics ; Protein Conformation ; Protein Domains/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Structure-Activity Relationship
Chemical Substances	DNA-Binding Proteins ; FUBP1 protein, human ; Nucleotides ; RNA-Binding Proteins ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2020-08-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-69832-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Image-Based Annotation of Chemogenomic Libraries for Phenotypic Screening.

Tjaden, Amelie / Chaikuad, Apirat / Kowarz, Eric / Marschalek, Rolf / Knapp, Stefan / Schröder, Martin / Müller, Susanne

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 4

Abstract: Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation of identified hits often poses a challenge. The development of small molecules with ... ...

Abstract	Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation of identified hits often poses a challenge. The development of small molecules with narrow or exclusive target selectivity such as chemical probes and chemogenomic (CG) libraries, greatly diminishes this challenge, but non-specific effects caused by compound toxicity or interference with basic cellular functions still pose a problem to associate phenotypic readouts with molecular targets. Hence, each compound should ideally be comprehensively characterized regarding its effects on general cell functions. Here, we report an optimized live-cell multiplexed assay that classifies cells based on nuclear morphology, presenting an excellent indicator for cellular responses such as early apoptosis and necrosis. This basic readout in combination with the detection of other general cell damaging activities of small molecules such as changes in cytoskeletal morphology, cell cycle and mitochondrial health provides a comprehensive time-dependent characterization of the effect of small molecules on cellular health in a single experiment. The developed high-content assay offers multi-dimensional comprehensive characterization that can be used to delineate generic effects regarding cell functions and cell viability, allowing an assessment of compound suitability for subsequent detailed phenotypic and mechanistic studies.
MeSH term(s)	Cell Cycle/drug effects ; Cell Cycle/genetics ; Cell Line, Tumor ; Drug Discovery/methods ; Drug Evaluation, Preclinical/methods ; Genomics/methods ; High-Throughput Screening Assays/methods ; Humans ; Molecular Imaging/methods ; Reproducibility of Results ; Small Molecule Libraries ; Staining and Labeling
Chemical Substances	Small Molecule Libraries
Language	English
Publishing date	2022-02-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27041439
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Article ; Online: Design of a Potent TLX Agonist by Rational Fragment Fusion.

Faudone, Giuseppe / Zhubi, Rezart / Celik, Fatih / Knapp, Stefan / Chaikuad, Apirat / Heering, Jan / Merk, Daniel

Journal of medicinal chemistry

2022 Volume 65, Issue 3, Page(s) 2288–2296

Abstract: As a master regulator of neurogenesis, the orphan nuclear receptor tailless homologue (TLX, NR2E1) maintains neuronal stem cell homeostasis by acting as a transcriptional repressor of tumor suppressor genes. It is hence considered as an appealing target ... ...

Abstract	As a master regulator of neurogenesis, the orphan nuclear receptor tailless homologue (TLX, NR2E1) maintains neuronal stem cell homeostasis by acting as a transcriptional repressor of tumor suppressor genes. It is hence considered as an appealing target for the treatment of neurodegenerative diseases, but a lack of potent TLX modulators as tools to probe pharmacological TLX control hinders further validation of its promising potential. Here, we report the development of a potent TLX agonist based on fragment screening, pharmacophore modeling, and fragment fusion. Pharmacophore similarity of a fragment screening hit and the TLX ligand ccrp2 provided a rational basis for fragment linkage, which resulted in several TLX activator scaffolds. Among them, the fused compound
MeSH term(s)	Animals ; Cell Survival/drug effects ; Drug Design ; Drug Stability ; HEK293 Cells ; Humans ; Ligands ; Microsomes, Liver/metabolism ; Orphan Nuclear Receptors/agonists ; Orphan Nuclear Receptors/metabolism ; Piperazine/chemistry ; Piperazine/metabolism ; Piperazine/pharmacology ; Protein Binding ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship
Chemical Substances	Ligands ; NR2E1 protein, human ; Orphan Nuclear Receptors ; Piperazine (1RTM4PAL0V)
Language	English
Publishing date	2022-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c01757
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