@article{SchoeneggeGallionPicardetal.2017, author = {Sch{\"o}negge, Anne-Marie and Gallion, Jonathan and Picard, Louis-Philippe and Wilkins, Angela D. and Le Gouill, Christian and Audet, Martin and Stallaert, Wayne and Lohse, Martin J. and Kimmel, Marek and Lichtarge, Olivier and Bouvier, Michel}, title = {Evolutionary action and structural basis of the allosteric switch controlling β\(_2\)AR functional selectivity}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, doi = {10.1038/s41467-017-02257-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172268}, year = {2017}, abstract = {Functional selectivity of G-protein-coupled receptors is believed to originate from ligand-specific conformations that activate only subsets of signaling effectors. In this study, to identify molecular motifs playing important roles in transducing ligand binding into distinct signaling responses, we combined in silico evolutionary lineage analysis and structure-guided site-directed mutagenesis with large-scale functional signaling characterization and non-negative matrix factorization clustering of signaling profiles. Clustering based on the signaling profiles of 28 variants of the β\(_2\)-adrenergic receptor reveals three clearly distinct phenotypical clusters, showing selective impairments of either the Gi or βarrestin/endocytosis pathways with no effect on Gs activation. Robustness of the results is confirmed using simulation-based error propagation. The structural changes resulting from functionally biasing mutations centered around the DRY, NPxxY, and PIF motifs, selectively linking these micro-switches to unique signaling profiles. Our data identify different receptor regions that are important for the stabilization of distinct conformations underlying functional selectivity.}, language = {en} } @article{IsaacsMikasiObasaetal.2020, author = {Isaacs, Darren and Mikasi, Sello Given and Obasa, Adetayo Emmanuel and Ikomey, George Mondinde and Shityakov, Sergey and Cloete, Ruben and Jacobs, Graeme Brendon}, title = {Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors}, series = {Viruses}, volume = {12}, journal = {Viruses}, number = {9}, issn = {1999-4915}, doi = {10.3390/v12090936}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211170}, year = {2020}, abstract = {The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-na{\"i}ve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.}, language = {en} } @article{FergerBanKrošletal.2021, author = {Ferger, Matthias and Ban, Željka and Krošl, Ivona and Tomić, Sanja and Dietrich, Lena and Lorenzen, Sabine and Rauch, Florian and Sieh, Daniel and Friedrich, Alexandra and Griesbeck, Stefanie and Kenđel, Adriana and Miljanić, Snežana and Piantanida, Ivo and Marder, Todd B.}, title = {Bis(phenylethynyl)arene Linkers in Tetracationic Bis-triarylborane Chromophores Control Fluorimetric and Raman Sensing of Various DNAs and RNAs}, series = {Chemistry-A European Journal}, volume = {27}, journal = {Chemistry-A European Journal}, number = {16}, doi = {10.1002/chem.202005141}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256717}, pages = {5142-5159}, year = {2021}, abstract = {We report four new luminescent tetracationic bis-triarylborane DNA and RNA sensors that show high binding affinities, in several cases even in the nanomolar range. Three of the compounds contain substituted, highly emissive and structurally flexible bis(2,6-dimethylphenyl-4-ethynyl)arene linkers (3: arene=5,5′-2,2′-bithiophene; 4: arene=1,4-benzene; 5: arene=9,10-anthracene) between the two boryl moieties and serve as efficient dual Raman and fluorescence chromophores. The shorter analogue 6 employs 9,10-anthracene as the linker and demonstrates the importance of an adequate linker length with a certain level of flexibility by exhibiting generally lower binding affinities than 3-5. Pronounced aggregation-deaggregation processes are observed in fluorimetric titration experiments with DNA for compounds 3 and 5. Molecular modelling of complexes of 5 with AT-DNA, suggest the minor groove as the dominant binding site for monomeric 5, but demonstrate that dimers of 5 can also be accommodated. Strong SERS responses for 3-5 versus a very weak response for 6, particularly the strong signals from anthracene itself observed for 5 but not for 6, demonstrate the importance of triple bonds for strong Raman activity in molecules of this compound class. The energy of the characteristic stretching vibration of the C≡C bonds is significantly dependent on the aromatic moiety between the triple bonds. The insertion of aromatic moieties between two C≡C bonds thus offers an alternative design for dual Raman and fluorescence chromophores, applicable in multiplex biological Raman imaging.}, language = {en} } @article{WilhelmsBroscheitShityakov2023, author = {Wilhelms, Benedikt and Broscheit, Jens and Shityakov, Sergey}, title = {Chemical analysis and molecular modelling of cyclodextrin-formulated propofol and its sodium salt to improve drug solubility, stability and pharmacokinetics (cytogenotoxicity)}, series = {Pharmaceuticals}, volume = {16}, journal = {Pharmaceuticals}, number = {5}, issn = {1424-8247}, doi = {10.3390/ph16050667}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313705}, year = {2023}, abstract = {Propofol is a widely used general anesthetic in clinical practice, but its use is limited by its water-insoluble nature and associated pharmacokinetic and pharmacodynamic limitations. Therefore, researchers have been searching for alternative formulations to lipid emulsion to address the remaining side effects. In this study, novel formulations for propofol and its sodium salt Na-propofolat were designed and tested using the amphiphilic cyclodextrin (CD) derivative hydroxypropyl-β-cyclodextrin (HPβCD). The study found that spectroscopic and calorimetric measurements suggested complex formation between propofol/Na-propofolate and HPβCD, which was confirmed by the absence of an evaporation peak and different glass transition temperatures. Moreover, the formulated compounds showed no cytotoxicity and genotoxicity compared to the reference. The molecular modeling simulations based on molecular docking predicted a higher affinity for propofol/HPβCD than for Na-propofolate/HPβCD, as the former complex was more stable. This finding was further confirmed by high-performance liquid chromatography. In conclusion, the CD-based formulations of propofol and its sodium salt may be a promising option and a plausible alternative to conventional lipid emulsions.}, language = {en} }