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1.
Dr. Barbara Wienen-Schmidt Matthias Oebbeke Dr. Khang Ngo Prof. Dr. Andreas Heine Prof. Dr. Gerhard Klebe 《ChemMedChem》2021,16(1):292-300
In lead optimization, protein crystallography is an indispensable tool to analyze drug binding. Binding modes and non-covalent interaction inventories are essential to design follow-up synthesis candidates. Two protocols are commonly applied to produce protein–ligand complexes: cocrystallization and soaking. Because of its time and cost effectiveness, soaking is the more popular method. Taking eight ligand hinge binders of protein kinase A, we demonstrate that cocrystallization is superior. Particularly for flexible proteins, such as kinases, and larger ligands cocrystallization captures more reliable the correct binding pose and induced protein adaptations. The geometrical discrepancies between soaking and cocrystallization appear smaller for fragment-sized ligands. For larger flexible ligands that trigger conformational changes of the protein, soaking can be misleading and underestimates the number of possible polar interactions due to inadequate, highly impaired positions of protein amino-acid side and main chain atoms. Thus, if applicable cocrystallization should be the gold standard to study protein–ligand complexes. 相似文献
2.
Dr. Markella Konstantinidou Francesca Magari Fandi Sutanto Dr. Jörg Haupenthal Dr. Varsha R. Jumde Dr. M. Yagiz Ünver Prof. Dr. Andreas Heine Dr. Carlos Jamie Camacho Prof. Dr. Anna K. H. Hirsch Prof. Dr. Gerhard Klebe Prof. Dr. Alexander Dömling 《ChemMedChem》2020,15(8):680-684
Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases. 相似文献
3.
In the course of classical optics manufacturing glass components are in permanent direct contact with aqueous operating materials. Such contact leads to a certain absorption of water and hydrogenous compounds that may induce severe glass defects. In this contribution, absorption of hydrogen and other contaminants during grinding of glass was observed and qualitatively detected via laser‐induced breakdown spectroscopy. It is shown that hydrogen, calcium, magnesium, and carbon are implanted into the glass surface where the contaminant concentration increases over grinding time or contact time of the glass surface with water and the grinding tool, respectively. The contaminants hydrogen, calcium, and magnesium can be attributed to the water used as lubricant. In contrast, carbon most likely originates from wear debris of the used silicon carbide grinding pads. Several possible mechanisms that lead to such surface contamination of glasses during grinding – diffusion, accumulation in micro cracks as well as the formation of hydrated silica – are finally introduced. 相似文献
4.
Dr. Simon Schramm Luca Agnetta Dr. Marcel Bermudez Hubert Gerwe Matthias Irmen Dr. Janine Holze Dr. Timo Littmann Prof. Gerhard Wolber Dr. Christian Tränkle Prof. Michael Decker 《ChemMedChem》2019,14(14):1349-1358
Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1′-(2-tolyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M1-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy. 相似文献
5.
6.
Daniela Fogli Antonio Piccinno Stefan Carmien Gerhard Fischer 《Behaviour & Information Technology》2020,39(1):27-46
ABSTRACTThe digital age of the future is ‘not out there to be discovered’, but it needs to be ‘designed’. The design challenge has to address questions about how we want to live, work, and learn (as individuals and as communities) and what we value and appreciate, e.g.: reflecting on quality of life and creating inclusive societies. An overriding design trade-off for the digital age is whether new developments will increase the digital divide or will create more inclusive societies. Sustaining inclusive societies means allowing people of all ages and all abilities to exploit information technologies for personally meaningful activities. Meta-design fosters the design of socio-technical environments that end-user developers can modify and evolve at use time to improve their quality of life and favour their inclusion in the society. This paper describes three case studies in the domain of assistive technologies in which end users themselves cannot act as end-user developers, but someone else (e.g.: a caregiver or a clinician) must accept this role requiring multi-tiered architectures. The design trade-offs and requirements for meta-design identified in the context of the case studies and other researchers’ projects are described to inform the development of future socio-technical environments focused on social inclusion. 相似文献
7.
Knowledge‐Based Conceptual Synthesis of Industrial‐Scale Downstream Processes for Biochemical Products 下载免费PDF全文
Karin Backhaus Mirka Lochmüller Markus Christian Arndt Ole Riechert Gerhard Schembecker 《化学工程与技术》2015,38(3):537-546
A generic, knowledge‐based guideline assisting downstream process synthesis for biochemical products is presented. It offers process designers a structured process design methodology supporting them in capturing potentially relevant information, which might be beyond their expertise. The guideline is based on heuristic knowledge which was collected, structured in a generic way, and clearly represented. The generation of alternative downstream routes as starting points for experiments, simulation, and cost calculation is hereby accelerated. The application of the guideline is demonstrated on the example of penicillin V downstream processing from fermentation broth. 相似文献
8.
Dr. Daniel Feder Dr. Siti H. Mohd-Pahmi Dr. Waleed M. Hussein Prof. Luke W. Guddat Prof. Ross P. McGeary Prof. Gerhard Schenk 《ChemMedChem》2021,16(21):3342-3359
Metallohydrolases form a large group of enzymes that have fundamental importance in a broad range of biological functions. Among them, the purple acid phosphatases (PAPs) have gained attention due to their crucial role in the acquisition and use of phosphate by plants and also as a promising target for novel treatments of bone-related disorders and cancer. To date, no crystal structure of a mammalian PAP with drug-like molecules bound near the active site is available. Herein, we used a fragment-based design approach using structures of a mammalian PAP in complex with the MaybridgeTM fragment CC063346, the amino acid L-glutamine and the buffer molecule HEPES, as well as various solvent molecules to guide the design of highly potent and efficient mammalian PAP inhibitors. These inhibitors have improved aqueous solubility when compared to the clinically most promising PAP inhibitors available to date. Furthermore, drug-like fragments bound in newly discovered binding sites mapped out additional scaffolds for further inhibitor discovery, as well as scaffolds for the design of inhibitors with novel modes of action. 相似文献
9.
Rolf Trettin Klaus Freyer Gerhard Strauch Hanns-Christian Treutler Walter Gläßer 《Grundwasser》1999,4(1):3-10
Environmental isotopes such as 3 H, 2 H, 18 O, 34 S and 222 Rn were applied to characterize relationships within and between ground and surface waters in two developing mining lakes. Using a two-component-model the portion of saline waters ascending through the lake bottom into the lakes was estimated. Similarly the contribution of pyritic sulphur participating in the lake sulfate has been assessed. Locally, the lakes are hydrochemically stratified. Mixing processes are reflected by all isotopes mentioned above. δ 13 C DIC values of the most mineralized lake water did not correspond with those of deep groundwater from Zechstein strata revailing additional effects such as CO 2 production. 222 Rn was checked for assessing groundwater fluxes through the lake bottom. 222 Rn was found in lake water regions with elevated salt contens but being always in an equilibrium with radium (excepting the sediment-lake water interface). Thus, radium must be taken in consideration in order to interprete radon values in saline groundwaters. 相似文献
10.
Mario Cueto Abel Farroni Silvio D. Rodríguez Regine Schoenlechner Gerhard Schleining María del Pilar Buera 《Food and Bioprocess Technology》2018,11(8):1586-1595
Spectral analysis employing multivariate techniques was employed to differentiate plain maize flours from formulations containing maize with added milled chia or quinoa seeds for producing cereal breakfast extrudates. The physicochemical changes of the enriched formulations due to processing stages and formulation were evaluated by using FTIR and chemometric analysis, which allowed a rapid and non-destructive discrimination between sample processing and compositional aspects. Specific IR frequencies were selected which provided highest sample discrimination. Selected IR absorbance relationships at those specific wavenumbers were useful to track changes promoted by extrusion for carbohydrates, proteins, and lipids. The complexes between amylose and lipids, that takes place during extrusion, underwent distinctive changes as confirmed by XRD. The crystallinity loss, after extrusion (with an average value of 50%), shows evidence of amylose-lipid complexes formation of type Eh and Vh. Correlations between the textural behavior, composition, and selected FTIR indices were obtained. 相似文献