Stefan Günther

Stefan Günther
University of Freiburg | Albert-Ludwigs-Universität Freiburg · Pharmaceutical Bioinformatics

About

143
Publications
25,610
Reads
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3,637
Citations
Citations since 2016
82 Research Items
2491 Citations
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
Additional affiliations
November 2009 - October 2015
University of Freiburg
Position
  • Junior-Professor

Publications

Publications (143)
Article
Full-text available
Host cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is facilitated via priming of its spike glycoprotein by the human transmembrane protease serine 2 (TMPRSS2). Although camostat and nafamostat are two highly potent covalent TMPRSS2 inhibitors, they nevertheless did not hold promise in COVID-19 clinical trials, presumabl...
Article
Bone marrow (BM) hematopoietic stem cells (HSCs) are vital for the lifelong maintenance of the hematopoietic system. Experimental mice are housed in germ-free facilities, where the top of the hematopoietic hierarchy is occupied by dormant HSCs, which reversibly exit quiescence during stress. The existence of dormant HSC in humans remains debatable....
Article
Full-text available
Newly discovered functional relationships of (bio-)molecules are a key component in molecular biology and life science research. Especially in the drug discovery field, knowledge of how small molecules associate with proteins plays a fundamental role in understanding how drugs or metabolites can affect cells, tissues, and human metabolism. Finding...
Article
Full-text available
Energy-converting NADH:ubiquinone oxidoreductase, respiratory complex I, is essential for cellular energy metabolism coupling NADH oxidation to proton translocation. The mechanism of proton translocation by complex I is still under debate. Its membrane arm contains an unusual central axis of polar and charged amino acid residues connecting the quin...
Article
Full-text available
Bone marrow haematopoietic stem cells (HSCs) are vital for lifelong maintenance of healthy haematopoiesis. In inbred mice housed in gnotobiotic facilities, the top of the haematopoietic hierarchy is occupied by dormant HSCs, which reversibly exit quiescence during stress. Whether HSC dormancy exists in humans remains debatable. Here, using single-c...
Article
Full-text available
In-silico methods for the prediction of epitopes can support and improve workflows for vaccine design, antibody production, and disease therapy. So far, the scope of B cell and T cell epitope prediction has been directed exclusively towards peptidic antigens. Nevertheless, various non-peptidic molecular classes can be recognized by immune cells. Th...
Article
Full-text available
Cytochrome bd quinol:O 2 oxidoreductases are respiratory terminal oxidases so far only identified in prokaryotes, including several pathogenic bacteria. Escherichia coli contains two bd oxidases of which only the bd -I type is structurally characterized. Here, we report the structure of the Escherichia coli cytochrome bd -II type oxidase with the b...
Article
While aromatic cages have extensively been investigated in the context of structural biology, molecular recognition, and drug discovery, there exist to date no comprehensive resource for proteins sharing this conserved structural motif. To this end, we parsed the Protein Data Bank and thus constructed the Aromatic Cage Database (AroCageDB), a datab...
Article
Full-text available
NADH:ubiquinone oxidoreductase, respiratory complex I, plays a central role in cellular energy metabolism. As a major source of reactive oxygen species (ROS) it affects ageing and mitochondrial dysfunction. The novel inhibitor NADH-OH specifically blocks NADH oxidation and ROS production by complex I in nM concentrations. Attempts to elucidate its...
Article
Full-text available
NADH:ubiquinone oxidoreductase, respiratory complex I, plays a central role in cellular energy metabolism. As a major source of reactive oxygen species (ROS) it affects ageing and mitochondrial dysfunction. The novel inhibitor NADH‐OH specifically blocks NADH oxidation and ROS production by complex I in nM concentrations. Attempts to elucidate its...
Article
Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor XD14 and well-established HDAC inhibito...
Article
Full-text available
In recent years, the drug discovery paradigm has shifted toward compounds that covalently modify disease-associated target proteins, because they tend to possess high potency, selectivity, and duration of action. The rational design of novel targeted covalent inhibitors (TCIs) typically starts from resolved macromolecular structures of target prote...
Book
Full-text available
Vol. 2 of Chemoinformatics of Natural Products introduces the reader to the currently available tools for toxicity and drug property prediction, an enumeration of compounds, scaffolds and functional groups in nature, computational methods for lead identifi cation, metabolite biosynthesis, etc. Selected case studies and hands-on tutorial exercises h...
Article
Bioactive compounds oftentimes bind to several target proteins, thereby exhibiting polypharmacology. Experimentally determining these interactions is however laborious, and structure-based virtual screening (SBVS) of bioactive compounds could expedite drug discovery by prioritizing hits for experimental validation. Here, we present ePharmaLib, a li...
Article
In the quest to know why natural products (NPs) have often been considered as privileged scaffolds for drug discovery purposes, many investigations into the differences between NPs and synthetic compounds have been carried out. Several attempts to answer this question have led to the investigation of the atomic composition, scaffolds and functional...
Preprint
Full-text available
In-silico methods for the prediction of epitopes can support and improve workflows for vaccine design, antibody production, and disease therapy. So far, the scope of B cell and T cell epitope prediction has been directed exclusively towards peptidic antigens. Nevertheless, various non-peptidic molecular classes can be recognized by immune cells. Th...
Article
Full-text available
Rishirilides are a group of PKS II secondary metabolites produced by Streptomyces bottropensis Gö C4/4. Biosynthetic studies in the past have elucidated early and late steps of rishirilide biosynthesis. This work is aiming to solve the remaining steps in the rishirilide biosynthesis. Inactivation of the cyclase gene rslC3 in Streptomyces bottropens...
Article
Full-text available
The T cell antigen receptor (TCR) is expressed on T cells, which orchestrate adaptive immune responses. It is composed of the ligand-binding clonotypic TCRαβ heterodimer and the non-covalently bound invariant signal-transducing CD3 complex. Among the CD3 subunits, the CD3ε cytoplasmic tail contains binding motifs for the Src family kinase, Lck, and...
Article
Full-text available
Cyperus rotundus L. (Nutgrass, family Cyperaceae) is a notorious weed which is widespread in temperate tropical and subtropical regions of the world. Owing to its richness and potent pharmacological activities, efforts have been devoted to identify its bioactive constituents. Since 1965, a total of about 192 compounds including terpenoids, flavonoi...
Article
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
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Microorganisms produce secondary metabolites with a remarkable range of bioactive properties. The constantly increasing amount of published genomic data provides the opportunity for efficient identification of biosynthetic gene clusters by genome mining. On the other hand, for many natural products with resolved structures, the encoding biosyntheti...
Article
Influenza virus causes influenza, an infectious disease. The symptoms can range from mild to severe. Severe influenza infections have historically led to 250,000 to 500,000 deaths per year. Influenza viruses can be broadly classified into four types as A, B, C, and D. They are structurally similar, and place high demands on drugs. The heterotrimeri...
Article
Full-text available
Nearly half of the world’s population relies on combustion of solid biofuels to cover fundamental energy demands. Epidemiologic data demonstrate that particularly long-term emissions adversely affect human health. However, pathological molecular mechanisms are insufficiently characterized. Here we demonstrate that long-term exposure to fine particu...
Article
Full-text available
Antimicrobial resistance is an emerging global health threat necessitating the rapid development of novel antimicrobials. Remarkably, the vast majority of currently available antibiotics are natural products (NPs) isolated from streptomycetes, soil-dwelling bacteria of the genus Streptomyces. However, there is still a huge reservoir of streptomycet...
Article
Full-text available
Medicinal plants have widely been used in the traditional treatment of ailments and have been proven effective. Their contribution still holds an important place in modern drug discovery due to their chemical, and biological diversities. However, the poor documentation of traditional medicine, in developing African countries for instance, can lead...
Article
Full-text available
Medicinal plants have widely been used in the traditional treatment of ailments and have been proven effective. Their contribution still holds an important place in modern drug discovery due to their chemical, and biological diversities. However, the poor documentation of traditional medicine, in developing African countries for instance, can lead...
Article
Histone methylation reader proteins (HMRPs) regulate gene transcription by recognizing, at their “aromatic cage” domains, various Lys/Arg methylation states on histone tails. Since epigenetic dysregulation underlies a wide range of diseases, HMRPs have thus become attractive drug targets. However, structure-based efforts in targeting them are still...
Article
Full-text available
Initiation of T cell antigen receptor (TCR) signaling involves phosphorylation of CD3 cytoplasmic tails by the tyrosine kinase Lck. How Lck is recruited to the TCR to initiate signaling is not well known. We report a previously unknown binding motif in the CD3ε cytoplasmic tail that interacts in a noncanonical mode with the Lck SH3 domain: the rece...
Article
Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemic...
Article
Full-text available
Motivation Much effort has been invested in the identification of protein-protein interactions using text mining and machine learning methods. The extraction of functional relationships between chemical compounds and proteins from literature has received much less attention, and no ready-to-use open-source software is so far available for this task...
Chapter
One major challenge in natural product (NP) discovery is the determination of the chemical structure of unknown metabolites using automated software tools from either GC-mass spectrometry (MS) or liquid chromatography-MS/MS data only. This chapter reviews the existing spectral libraries and predictive computational tools used in MS-based untargeted...
Article
Initiation of T cell antigen receptor (TCR) signaling involves phosphorylation of CD3 cytoplasmic tails by the tyrosine kinase Lck. How Lck is recruited to the TCR to initiate signaling is not well known. We report a previously unknown binding motif in the CD3ε cytoplasmic tail that interacts in a noncanonical mode with the Lck SH3 domain: the rece...
Book
Full-text available
Volume 1 of Chemoinformatics of Natural Products lays down the fundamental concepts of chemical informatics and is exclusively dedicated to the investigation of natural products (NPs) or secondary metabolites (SMs), the main source of lead compounds for drug discovery. Several experts in the field, working in different continents and from diverse b...
Article
Full-text available
Natural products (NPs) are an indispensable source of drugs and they have a better coverage of the pharmacological space than synthetic compounds, owing to their high structural diversity. The prediction of their interaction profiles with druggable protein targets remains a major challenge in modern drug discovery. Experimental (off-)target predict...
Article
Full-text available
These authors contributed equally to this work. Citation details: Norval,L. W., Krämer,S. D., Gao,M. et al. KOFFI and Anabel 2.0-a new binding kinetics database and its integration in an open-source binding analysis software. Abstract The kinetics of featured interactions (KOFFI) database is a novel tool and resource for binding kinetics data from...
Preprint
In the quest to know why natural products (NPs) have often been considered as privileged scaffolds for drug discovery purposes many investigations into the differences between NPs and synthetic compounds have been carried out. Several attempts to answer this question have led to the investigation of the atomic composition, scaffolds and functional...
Preprint
Full-text available
Motivation: Much effort has been invested in the identification of protein-protein interactions using text mining and machine learning methods. The extraction of functional relationships between chemical compounds and proteins from literature has received much less attention, and no ready-to-use open-source software is so far available for this tas...
Article
One major challenge in natural product (NP) discovery is the determination of the chemical structure of unknown metabolites using automated software tools from either GC–mass spectrometry (MS) or liquid chromatography–MS/MS data only. This chapter reviews the existing spectral libraries and predictive computational tools used in MS-based untargeted...
Article
The cover feature picture shows a two‐faced clown twisting balloons into different shapes depending on which type of balloon he grabs. Similarly, the ketoreductase Tyl‐KR1 converts methylated keto esters diastereoselectively into either R,R‐ or S,S‐configured hydroxyesters, depending simply on the choice of ester moiety. In their communication, S....
Article
Streptomyces asterosporus DSM 41452 is a producer of the polyketide annimycin and the non-ribosomal depsipeptide WS9326A. This strain is also notable for exhibiting a bald phenotype that is devoid of spores and aerial mycelium when grown on solid media. Based on the similarity of the 16S rRNA sequence to Streptomyces calvus, the only known producer...
Chapter
Bromodomains (BRDs) are functional modules which recognize acetylated lysines on the surface of proteins. Such post‐translational modifications exist in thousands of human proteins and play a crucial role in diverse signaling networks. It has been shown that by recognizing acetylated lysines on histone tails, BRDs regulate the transcription of spec...
Article
Enzymes often convert both physiological and non‐physiological substrates with high stereoselectivity — yet, for some enzymes, opposite product chirality is observed. A possible explanation is the existence of hidden specificities becoming apparent when non‐physiological substrates confer different substrate–enzyme interactions than the physiologic...
Article
With the bromodomain (BRD) inhibitor JQ1, a remarkable success story of BRD4 as a novel drug target has been set off that yielded many anti‐cancer drugs that are now in clinical trials. But not all of the great prospects of BRDs as drug targets may become true. First evaluations of ongoing clinical trials revealed that treatment with BET‐inhibitors...
Article
Full-text available
In this work, we study the dynamics and the energetics of the all-atom structure of a neuronal-specific serine/threonine kinase c-Jun N-terminal kinase 3 (JNK3) in three states: unphosphorylated, phosphorylated, and ATP-bound phosphorylated. A series of 2 µs atomistic simulations followed by a conformational landscape mapping and a principal compon...
Poster
Full-text available
This is a poster describing shortly how RDKit is been utilized in Pharmaceutical Bioinformatics
Article
BET bromodomain inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms, and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. Here, we introduce XDM-CBP, a highly potent and...
Article
Full-text available
BET bromodomain inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms, and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. Here, we introduce XDM-CBP, a highly potent and...
Article
Within endocrine disruptor research, evaluation and interpretation of mixture effects and the predictive value for downstream responses still warrant more in-depth investigations. We used an estrogen receptor (ER)-mediated reporter gene assay (ER-CALUX®) and a cell proliferation assay (WST-1 assay), both based on the T47D breast cancer cell line, t...
Article
Exposure to particulate matter (PM) is recognized as a major health hazard, but molecular responses are still insufficiently described. We analyzed the epigenetic impact of ambient PM2.5 from biomass combustion on the methylome of primary human bronchial epithelial BEAS-2B cells using the Illumina HumanMethylation450 BeadChip. The transcriptome was...