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  1. Article: Details Matter in Structure-based Drug Design.

    Kuhn, Bernd / Peters, Jens-Uwe / Rudolph, Markus G / Mohr, Peter / Stahl, Martin / Tosstorff, Andreas

    Chimia

    2023  Volume 77, Issue 7-8, Page(s) 489–493

    Abstract: Successful structure-based drug design (SBDD) requires the optimization of interactions with the target protein and the minimization of ligand strain. Both factors are often modulated by small changes in the chemical structure which can lead to profound ... ...

    Abstract Successful structure-based drug design (SBDD) requires the optimization of interactions with the target protein and the minimization of ligand strain. Both factors are often modulated by small changes in the chemical structure which can lead to profound changes in the preferred conformation and interaction preferences of the ligand. We draw from examples of a Roche project targeting phosphodiesterase 10 to highlight that details matter in SBDD. Data mining in crystal structure databases can help to identify these sometimes subtle effects, but it is also a great resource to learn about molecular recognition in general and can be used as part of molecular design tools. We illustrate the use of the Cambridge Structural Database for identifying preferred structural motifs for intramolecular hydrogen bonding and of the Protein Data Bank for deriving propensities for protein-ligand interactions.
    MeSH term(s) Ligands ; Data Mining ; Databases, Factual ; Drug Design ; Learning
    Chemical Substances Ligands
    Language English
    Publishing date 2023-08-09
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1516-7
    ISSN 0009-4293
    ISSN 0009-4293
    DOI 10.2533/chimia.2023.489
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  2. Article ; Online: Structure of reverse gyrase with a minimal latch that supports ATP-dependent positive supercoiling without specific interactions with the topoisomerase domain.

    Mhaindarkar, Vaibhav P / Rasche, René / Kümmel, Daniel / Rudolph, Markus G / Klostermeier, Dagmar

    Acta crystallographica. Section D, Structural biology

    2023  Volume 79, Issue Pt 6, Page(s) 498–507

    Abstract: Reverse gyrase is the only topoisomerase that introduces positive supercoils into DNA in an ATP-dependent reaction. Positive DNA supercoiling becomes possible through the functional cooperation of the N-terminal helicase domain of reverse gyrase with its ...

    Abstract Reverse gyrase is the only topoisomerase that introduces positive supercoils into DNA in an ATP-dependent reaction. Positive DNA supercoiling becomes possible through the functional cooperation of the N-terminal helicase domain of reverse gyrase with its C-terminal type IA topoisomerase domain. This cooperation is mediated by a reverse-gyrase-specific insertion into the helicase domain termed the `latch'. The latch consists of a globular domain inserted at the top of a β-bulge loop that connects this globular part to the helicase domain. While the globular domain shows little conservation in sequence and length and is dispensable for DNA supercoiling, the β-bulge loop is required for supercoiling activity. It has previously been shown that the β-bulge loop constitutes a minimal latch that couples ATP-dependent processes in the helicase domain to DNA processing by the topoisomerase domain. Here, the crystal structure of Thermotoga maritima reverse gyrase with such a β-bulge loop as a minimal latch is reported. It is shown that the β-bulge loop supports ATP-dependent DNA supercoiling of reverse gyrase without engaging in specific interactions with the topoisomerase domain. When only a small latch or no latch is present, a helix in the nearby helicase domain of T. maritima reverse gyrase partially unfolds. Comparison of the sequences and predicted structures of latch regions in other reverse gyrases shows that neither sequence nor structure are decisive factors for latch functionality; instead, the decisive factors are likely to be electrostatics and plain steric bulk.
    MeSH term(s) Protein Structure, Tertiary ; DNA Topoisomerases, Type I/chemistry ; DNA Topoisomerases, Type I/genetics ; DNA Topoisomerases, Type I/metabolism ; DNA Helicases/chemistry ; DNA ; Adenosine Triphosphate
    Chemical Substances DNA reverse gyrase (EC 5.99.1.-) ; DNA Topoisomerases, Type I (EC 5.99.1.2) ; DNA Helicases (EC 3.6.4.-) ; DNA (9007-49-2) ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2023-05-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2968623-4
    ISSN 2059-7983 ; 0907-4449
    ISSN (online) 2059-7983
    ISSN 0907-4449
    DOI 10.1107/S2059798323002565
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  3. Article ; Online: Details Matter in Structure-based Drug Design

    Bernd Kuhn / Jens-Uwe Peters / Markus G. Rudolph / Peter Mohr / Martin Stahl / Andreas Tosstorff

    CHIMIA, Vol 77, Iss 7/

    2023  Volume 8

    Abstract: Successful structure-based drug design (SBDD) requires the optimization of interactions with the target protein and the minimization of ligand strain. Both factors are often modulated by small changes in the chemical structure which can lead to profound ... ...

    Abstract Successful structure-based drug design (SBDD) requires the optimization of interactions with the target protein and the minimization of ligand strain. Both factors are often modulated by small changes in the chemical structure which can lead to profound changes in the preferred conformation and interaction preferences of the ligand. We draw from examples of a Roche project targeting phosphodiesterase 10 to highlight that details matter in SBDD. Data mining in crystal structure databases can help to identify these sometimes subtle effects, but it is also a great resource to learn about molecular recognition in general and can be used as part of molecular design tools. We illustrate the use of the Cambridge Structural Database for identifying preferred structural motifs for intramolecular hydrogen bonding and of the Protein Data Bank for deriving propensities for protein-ligand interactions.
    Keywords Intramolecular hydrogen bond ; Ligand strain ; Molecular interactions ; PDE10 ; Chemistry ; QD1-999
    Subject code 500
    Language German
    Publishing date 2023-08-01T00:00:00Z
    Publisher Swiss Chemical Society
    Document type Article ; Online
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  4. Article: Discovery of a Series of Indane-Containing NBTIs with Activity against Multidrug-Resistant Gram-Negative Pathogens.

    Cumming, John G / Kreis, Lukas / Kühne, Holger / Wermuth, Roger / Vercruysse, Maarten / Kramer, Christian / Rudolph, Markus G / Xu, Zhiheng

    ACS medicinal chemistry letters

    2023  Volume 14, Issue 7, Page(s) 993–998

    Abstract: The rise of multidrug-resistant (MDR) Gram-negative bacteria is a major global health problem necessitating the discovery of new classes of antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) target the clinically validated bacterial type II ... ...

    Abstract The rise of multidrug-resistant (MDR) Gram-negative bacteria is a major global health problem necessitating the discovery of new classes of antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) target the clinically validated bacterial type II topoisomerases with a distinct binding site and mechanism of action to fluoroquinolone antibiotics, thus avoiding cross-resistance to this drug class. Here we report the discovery of a series of NBTIs incorporating a novel indane DNA binding moiety. X-ray cocrystal structures of compounds
    Language English
    Publishing date 2023-06-22
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.3c00187
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  5. Article ; Online: Clinical recommendations for the inpatient management of lower respiratory tract infections in children and adolescents with severe neurological impairment in Germany.

    Mauritz, Maximilian David / von Both, Ulrich / Dohna-Schwake, Christian / Gille, Christian / Hasan, Carola / Huebner, Johannes / Hufnagel, Markus / Knuf, Markus / Liese, Johannes G / Renk, Hanna / Rudolph, Henriette / Schulze-Sturm, Ulf / Simon, Arne / Stehling, Florian / Tenenbaum, Tobias / Zernikow, Boris

    European journal of pediatrics

    2024  Volume 183, Issue 3, Page(s) 987–999

    Abstract: Children and adolescents with severe neurological impairment (SNI) require specialized care due to their complex medical needs. In particular, these patients are often affected by severe and recurrent lower respiratory tract infections (LRTIs). These ... ...

    Abstract Children and adolescents with severe neurological impairment (SNI) require specialized care due to their complex medical needs. In particular, these patients are often affected by severe and recurrent lower respiratory tract infections (LRTIs). These infections, including viral and bacterial etiology, pose a significant risk to these patients, often resulting in respiratory insufficiency and long-term impairments. Using expert consensus, we developed clinical recommendations on the management of LRTIs in children and adolescents with SNI. These recommendations emphasize comprehensive multidisciplinary care and antibiotic stewardship. Initial treatment should involve symptomatic care, including hydration, antipyretics, oxygen therapy, and respiratory support. In bacterial LRTIs, antibiotic therapy is initiated based on the severity of the infection, with aminopenicillin plus a beta-lactamase inhibitor recommended for community-acquired LRTIs and piperacillin-tazobactam for patients with chronic lung disease or tracheostomy. Ongoing management includes regular evaluations, adjustments to antibiotic therapy based on pathogen identification, and optimization of supportive care. Implementation of these recommendations aims to improve the diagnosis and treatment of LRTIs in children and adolescents with SNI. What is Known: • Children and adolescents with severe neurological impairment are particularly affected by severe and recurrent lower respiratory tract infections (LRTIs). • The indication and choice of antibiotic therapy for bacterial LRTI is often difficult because there are no evidence-based treatment recommendations for this heterogeneous but vulnerable patient population; the frequent overuse of broad-spectrum or reserve antibiotics in this patient population increases selection pressure for multidrug-resistant pathogens. What is New: • The proposed recommendations provide a crucial framework for focused diagnostics and treatment of LRTIs in children and adolescents with severe neurological impairment. • Along with recommendations for comprehensive and multidisciplinary therapy and antibiotic stewardship, ethical and palliative care aspects are taken into account.
    MeSH term(s) Child ; Humans ; Adolescent ; Inpatients ; Respiratory Tract Infections/diagnosis ; Respiratory Tract Infections/drug therapy ; Anti-Bacterial Agents/therapeutic use ; Piperacillin, Tazobactam Drug Combination/therapeutic use ; Bacterial Infections/drug therapy ; Bacteria
    Chemical Substances Anti-Bacterial Agents ; Piperacillin, Tazobactam Drug Combination (157044-21-8)
    Language English
    Publishing date 2024-01-03
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 194196-3
    ISSN 1432-1076 ; 0340-6199 ; 0943-9676
    ISSN (online) 1432-1076
    ISSN 0340-6199 ; 0943-9676
    DOI 10.1007/s00431-023-05401-6
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  6. Article ; Online: A high quality, industrial data set for binding affinity prediction: performance comparison in different early drug discovery scenarios.

    Tosstorff, Andreas / Rudolph, Markus G / Cole, Jason C / Reutlinger, Michael / Kramer, Christian / Schaffhauser, Hervé / Nilly, Agnès / Flohr, Alexander / Kuhn, Bernd

    Journal of computer-aided molecular design

    2022  Volume 36, Issue 10, Page(s) 753–765

    Abstract: We release a new, high quality data set of 1162 PDE10A inhibitors with experimentally determined binding affinities together with 77 PDE10A X-ray co-crystal structures from a Roche legacy project. This data set is used to compare the performance of ... ...

    Abstract We release a new, high quality data set of 1162 PDE10A inhibitors with experimentally determined binding affinities together with 77 PDE10A X-ray co-crystal structures from a Roche legacy project. This data set is used to compare the performance of different 2D- and 3D-machine learning (ML) as well as empirical scoring functions for predicting binding affinities with high throughput. We simulate use cases that are relevant in the lead optimization phase of early drug discovery. ML methods perform well at interpolation, but poorly in extrapolation scenarios-which are most relevant to a real-world application. Moreover, we find that investing into the docking workflow for binding pose generation using multi-template docking is rewarded with an improved scoring performance. A combination of 2D-ML and 3D scoring using a modified piecewise linear potential shows best overall performance, combining information on the protein environment with learning from existing SAR data.
    MeSH term(s) Ligands ; Protein Binding ; Drug Discovery ; Proteins/chemistry ; Machine Learning ; Molecular Docking Simulation
    Chemical Substances Ligands ; Proteins
    Language English
    Publishing date 2022-09-25
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 808166-9
    ISSN 1573-4951 ; 0920-654X
    ISSN (online) 1573-4951
    ISSN 0920-654X
    DOI 10.1007/s10822-022-00478-x
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  7. Article ; Online: When core competence is not enough: functional interplay of the DEAD-box helicase core with ancillary domains and auxiliary factors in RNA binding and unwinding.

    Rudolph, Markus G / Klostermeier, Dagmar

    Biological chemistry

    2015  Volume 396, Issue 8, Page(s) 849–865

    Abstract: DEAD-box helicases catalyze RNA duplex unwinding in an ATP-dependent reaction. Members of the DEAD-box helicase family consist of a common helicase core formed by two RecA-like domains. According to the current mechanistic model for DEAD-box mediated RNA ...

    Abstract DEAD-box helicases catalyze RNA duplex unwinding in an ATP-dependent reaction. Members of the DEAD-box helicase family consist of a common helicase core formed by two RecA-like domains. According to the current mechanistic model for DEAD-box mediated RNA unwinding, binding of RNA and ATP triggers a conformational change of the helicase core, and leads to formation of a compact, closed state. In the closed conformation, the two parts of the active site for ATP hydrolysis and of the RNA binding site, residing on the two RecA domains, become aligned. Closing of the helicase core is coupled to a deformation of the RNA backbone and destabilization of the RNA duplex, allowing for dissociation of one of the strands. The second strand remains bound to the helicase core until ATP hydrolysis and product release lead to re-opening of the core. The concomitant disruption of the RNA binding site causes dissociation of the second strand. The activity of the helicase core can be modulated by interaction partners, and by flanking N- and C-terminal domains. A number of C-terminal flanking regions have been implicated in RNA binding: RNA recognition motifs (RRM) typically mediate sequence-specific RNA binding, whereas positively charged, unstructured regions provide binding sites for structured RNA, without sequence-specificity. Interaction partners modulate RNA binding to the core, or bind to RNA regions emanating from the core. The functional interplay of the helicase core and ancillary domains or interaction partners in RNA binding and unwinding is not entirely understood. This review summarizes our current knowledge on RNA binding to the DEAD-box helicase core and the roles of ancillary domains and interaction partners in RNA binding and unwinding by DEAD-box proteins.
    MeSH term(s) Adenosine Triphosphate/metabolism ; Binding Sites ; DEAD-box RNA Helicases/metabolism ; Hydrolysis ; Nucleic Acid Conformation ; Protein Binding ; Protein Structure, Tertiary ; RNA/chemistry ; RNA/metabolism
    Chemical Substances RNA (63231-63-0) ; Adenosine Triphosphate (8L70Q75FXE) ; DEAD-box RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2015-08
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1334659-3
    ISSN 1437-4315 ; 1431-6730 ; 1432-0355
    ISSN (online) 1437-4315
    ISSN 1431-6730 ; 1432-0355
    DOI 10.1515/hsz-2014-0277
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  8. Article ; Online: Shallow defects and variable photoluminescence decay times up to 280 µs in triple-cation perovskites.

    Yuan, Ye / Yan, Genghua / Dreessen, Chris / Rudolph, Toby / Hülsbeck, Markus / Klingebiel, Benjamin / Ye, Jiajiu / Rau, Uwe / Kirchartz, Thomas

    Nature materials

    2024  Volume 23, Issue 3, Page(s) 391–397

    Abstract: Quantifying recombination in halide perovskites is a crucial prerequisite to control and improve the performance of perovskite-based solar cells. While both steady-state and transient photoluminescence are frequently used to assess recombination in ... ...

    Abstract Quantifying recombination in halide perovskites is a crucial prerequisite to control and improve the performance of perovskite-based solar cells. While both steady-state and transient photoluminescence are frequently used to assess recombination in perovskite absorbers, quantitative analyses within a consistent model are seldom reported. We use transient photoluminescence measurements with a large dynamic range of more than ten orders of magnitude on triple-cation perovskite films showing long-lived photoluminescence transients featuring continuously changing decay times that range from tens of nanoseconds to hundreds of microseconds. We quantitatively explain both the transient and steady-state photoluminescence with the presence of a high density of shallow defects and consequent high rates of charge carrier trapping, thereby showing that deep defects do not affect the recombination dynamics. The complex carrier kinetics caused by emission and recombination processes via shallow defects imply that the reporting of only single lifetime values, as is routinely done in the literature, is meaningless for such materials. We show that the features indicative for shallow defects seen in the bare films remain dominant in finished devices and are therefore also crucial to understanding the performance of perovskite solar cells.
    Language English
    Publishing date 2024-01-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 2088679-2
    ISSN 1476-4660 ; 1476-1122
    ISSN (online) 1476-4660
    ISSN 1476-1122
    DOI 10.1038/s41563-023-01771-2
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  9. Article ; Online: Circulating extracellular vesicles as biomarker for diagnosis, prognosis and monitoring in glioblastoma patients.

    Ricklefs, Franz L / Wollmann, Kathrin / Salviano-Silva, Amanda / Drexler, Richard / Maire, Cecile L / Kaul, Michael G / Reimer, Rudolph / Schüller, Ulrich / Heinemann, Sarina / Kolbe, Katharina / Mummert, Tobias / Glatzel, Markus / Peine, Sven / Gempt, Jens / Westphal, Manfred / Dührsen, Lasse / Lamszus, Katrin

    Neuro-oncology

    2024  

    Abstract: Background: Extracellular vesicles (EVs) obtained by noninvasive liquid biopsy from patient blood can serve as biomarkers. Here, we investigated the potential of circulating plasma EVs to serve as an indicator in the diagnosis, prognosis and treatment ... ...

    Abstract Background: Extracellular vesicles (EVs) obtained by noninvasive liquid biopsy from patient blood can serve as biomarkers. Here, we investigated the potential of circulating plasma EVs to serve as an indicator in the diagnosis, prognosis and treatment response of glioblastoma patients.
    Methods: Plasma samples were collected from glioblastoma patients at multiple timepoints before and after surgery. EV concentrations were measured by nanoparticle tracking analysis and imaging flow cytometry. Tumor burden and edema were quantified by 3D reconstruction. EVs and tumors were further monitored in glioma-bearing mice.
    Results: Glioblastoma patients displayed a 5.5-fold increase in circulating EVs compared to healthy donors (p < 0.0001). Patients with higher EV levels had a significantly shorter overall survival and progression-free survival than patients with lower levels, and the plasma EV concentration was an independent prognostic parameter for overall survival. EV levels correlated with the extent of peritumoral FLAIR hyperintensity but not with the size of the contrast-enhancing tumor, and similar findings were obtained in mice. Postoperatively, EV concentrations decreased rapidly back to normal levels, and the magnitude of the decline was associated with the extent of tumor resection. EV levels remained low during stable disease, but increased again upon tumor recurrence. In some patients, EV resurgence preceded the magnetic resonance imaging (MRI) detectability of tumor relapse.
    Conclusions: Our findings suggest that leakiness of the blood-brain barrier may primarily be responsible for the high circulating EV concentrations in glioblastoma patients. Elevated EVs reflect tumor presence, and their quantification may thus be valuable in assessing disease activity.
    Language English
    Publishing date 2024-04-03
    Publishing country England
    Document type Journal Article
    ZDB-ID 2028601-6
    ISSN 1523-5866 ; 1522-8517
    ISSN (online) 1523-5866
    ISSN 1522-8517
    DOI 10.1093/neuonc/noae068
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  10. Article ; Online: Mapping the spectrum of conformational states of the DNA- and C-gates in Bacillus subtilis gyrase.

    Rudolph, Markus G / Klostermeier, Dagmar

    Journal of molecular biology

    2013  Volume 425, Issue 15, Page(s) 2632–2640

    Abstract: Type II DNA topoisomerases alter the supercoiling state of DNA in an ATP-dependent fashion that requires large conformational changes. The directionality of DNA strand transfer is controlled by three transient protein interfaces, termed the N-gate, DNA- ... ...

    Abstract Type II DNA topoisomerases alter the supercoiling state of DNA in an ATP-dependent fashion that requires large conformational changes. The directionality of DNA strand transfer is controlled by three transient protein interfaces, termed the N-gate, DNA-gate, and C-gate. Bacterial gyrase is a type II DNA topoisomerase of A2B2 composition. The N-gate is formed by the two GyrB subunits and the GyrA subunits form the DNA- and C-gates. In structures of type II topoisomerase fragments, the DNA- and C-gates delimit a cavity for DNA and can be open or closed. However, the conformational space accessible has not yet been mapped. Here, we describe the crystal structure of the Bacillus subtilis DNA gyrase A subunit lacking the C-terminal DNA-wrapping domains. Five dimeric states of the GyrA N-terminal domain are observed, with their DNA- and C-gates either closed, or open to different extents. All of these conformations can in principle accommodate double-stranded DNA in the central cavity but only one conformation has its DNA-gate open wide enough for DNA to enter. The structure thus reflects the lower limit of DNA-gate opening that must occur during gyrase catalysis. The DNA-gate is formed by two flat surfaces, with few interactions. In contrast, the C-gate exhibits a highly undulated surface and forms a large number of interactions. None of the dimers in the crystal structures display an open C-gate that would allow DNA passage, in agreement with a transient opening of this gate during the catalytic cycle of DNA supercoiling.
    MeSH term(s) Bacillus subtilis/chemistry ; Bacillus subtilis/enzymology ; Crystallography, X-Ray ; DNA Gyrase/chemistry ; DNA Gyrase/metabolism ; Models, Molecular ; Protein Conformation ; Protein Multimerization
    Chemical Substances DNA Gyrase (EC 5.99.1.3)
    Language English
    Publishing date 2013-08-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2013.04.010
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