Hofmann B

References (8)

Title : Repurposing of 8-Hydroxyquinoline-based Butyrylcholinesterase and Cathepsin B Ligands as Potent Non-peptidic Deoxyribonuclease I Inhibitors - Gajic_2022_ChemMedChem__
Author(s) : Gajic M , Knez D , Sosic I , Mravljak J , Meden A , Kosak U , Leitzbach L , George S , Hofmann B , Zivkovic A , Steinhilber D , Stark H , Gobec S , Smelcerovic A , Anderluh M
Ref : ChemMedChem , : , 2022
Abstract : A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors, was screened in vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non-peptide DNase I inhibitors reported up to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35 microM and 50 nM, respectively, while 2 nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 microM and 20 microM, respectively. Selected derivatives were screened for various co-target binding affinities at dopamine D2 and D3, histamine H3 and H4 receptors and inhibition of 5-lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non-peptide DNase I inhibitors. The present study demonstrates that 8-hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds.
ESTHER : Gajic_2022_ChemMedChem__
PubMedSearch : Gajic_2022_ChemMedChem__
PubMedID: 34994078

Title : Design, Synthesis, and Structure-Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase - Hiesinger_2020_J.Med.Chem_63_11498
Author(s) : Hiesinger K , Kramer JS , Beyer S , Eckes T , Brunst S , Flauaus C , Wittmann SK , Weizel L , Kaiser A , Kretschmer SBM , George S , Angioni C , Heering J , Geisslinger G , Schubert-Zsilavecz M , Schmidtko A , Pogoryelov D , Pfeilschifter J , Hofmann B , Steinhilber D , Schwalm S , Proschak E
Ref : Journal of Medicinal Chemistry , 63 :11498 , 2020
Abstract : Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models.
ESTHER : Hiesinger_2020_J.Med.Chem_63_11498
PubMedSearch : Hiesinger_2020_J.Med.Chem_63_11498
PubMedID: 33044073
Gene_locus related to this paper: human-EPHX2

Title : Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase - Meirer_2016_Molecules_22_
Author(s) : Meirer K , Glatzel D , Kretschmer S , Wittmann SK , Hartmann M , Blocher R , Angioni C , Geisslinger G , Steinhilber D , Hofmann B , Furst R , Proschak E
Ref : Molecules , 22 : , 2016
Abstract : The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitor KM55 was rationally designed and synthesized. KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of KM55 in human whole blood and endothelial cells was investigated. KM55 potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. KM55 was also tested in a cell function-based assay. The compound significantly inhibited the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation.
ESTHER : Meirer_2016_Molecules_22_
PubMedSearch : Meirer_2016_Molecules_22_
PubMedID: 28036068

Title : Exploring the chemical space of multitarget ligands using aligned self-organizing maps - Achenbach_2013_ACS.Med.Chem.Lett_4_1169
Author(s) : Achenbach J , Klingler FM , Blocher R , Moser D , Hafner AK , Rodl CB , Kretschmer S , Kruger B , Lohr F , Stark H , Hofmann B , Steinhilber D , Proschak E
Ref : ACS Med Chem Lett , 4 :1169 , 2013
Abstract : Design of multitarget drugs and polypharmacological compounds has become popular during the past decade. However, the main approach to design such compounds is to link two selective ligands via a flexible linker. Although such chimeric ligands often have reasonable potency in vitro, the in vivo efficacy is low due to high molecular weight, low ligand efficiency, and poor pharmacokinetic profile. We developed an unprecedented in silico approach for fragment-based design of multitarget ligands. It relies on superposition of the chemical spaces related to the affinity on single targets represented by self-organizing maps. We used this approach for screening of molecular fragments, which bind to the enzymes 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH). Using STD-NMR and activity-based assays, we were able to identify fragments binding to both targets. Furthermore, we were able to expand one of the fragments to a potent dual inhibitor bearing a reasonable molecular weight (MW = 446) and high affinity to both targets (IC50 of 0.03 muM toward 5-LO and 0.17 muM toward sEH).
ESTHER : Achenbach_2013_ACS.Med.Chem.Lett_4_1169
PubMedSearch : Achenbach_2013_ACS.Med.Chem.Lett_4_1169
PubMedID: 24900624

Title : Synthesis and structure-activity relationship studies of novel dual inhibitors of soluble epoxide hydrolase and 5-lipoxygenase - Meirer_2013_J.Med.Chem_56_1777
Author(s) : Meirer K , Rodl CB , Wisniewska JM , George S , Hafner AK , Buscato EL , Klingler FM , Hahn S , Berressem D , Wittmann SK , Steinhilber D , Hofmann B , Proschak E
Ref : Journal of Medicinal Chemistry , 56 :1777 , 2013
Abstract : Current research leads to the assumption that drugs affecting more than one target could result in a more efficient treatment of diseases and fewer safety concerns. Administration of drugs inhibiting only one branch of the arachidonic acid cascade is usually accompanied by side effects. We therefore designed and synthesized a library of hybrid molecules incorporating an imidazo[1,2-a]pyridine and an urea moiety as novel soluble epoxide hydrolase (sEH)/5-lipoxygenase (5-LO) dual inhibitors. Evaluation of the compounds was accomplished by in vitro testing using recombinant enzyme assays.
ESTHER : Meirer_2013_J.Med.Chem_56_1777
PubMedSearch : Meirer_2013_J.Med.Chem_56_1777
PubMedID: 23356879

Title : Structural investigation of the cofactor-free chloroperoxidases - Hofmann_1998_J.Mol.Biol_279_889
Author(s) : Hofmann B , Tolzer S , Pelletier I , Altenbuchner J , van Pee KH , Hecht HJ
Ref : Journal of Molecular Biology , 279 :889 , 1998
Abstract : The structures of cofactor-free haloperoxidases from Streptomyces aureofaciens, Streptomyces lividans, and Pseudomonas fluorescens have been determined at resolutions between 1.9 A and 1.5 A. The structures of two enzymes complexed with benzoate or propionate identify the binding site for the organic acids which are required for the haloperoxidase activity. Based on these complexes and on the structure of an inactive variant, a reaction mechanism is proposed for the halogenation reaction with peroxoacid and hypohalous acid as reaction intermediates. Comparison of the structures suggests that a specific halide binding site is absent in the enzymes but that hydrophobic organic compounds may fit into the active site pocket for halogenation at preferential sites.
ESTHER : Hofmann_1998_J.Mol.Biol_279_889
PubMedSearch : Hofmann_1998_J.Mol.Biol_279_889
PubMedID: 9642069
Gene_locus related to this paper: psefl-cpoF , strau-brpa2 , strau-cpoT , strli-cpoL

Title : The nucleotide sequence of Saccharomyces cerevisiae chromosome XV - Dujon_1997_Nature_387_98
Author(s) : Dujon B , Albermann K , Aldea M , Alexandraki D , Ansorge W , Arino J , Benes V , Bohn C , Bolotin-Fukuhara M , Bordonne R , Boyer J , Camasses A , Casamayor A , Casas C , Cheret G , Cziepluch C , Daignan-Fornier B , Dang DV , de Haan M , Delius H , Durand P , Fairhead C , Feldmann H , Gaillon L , Galisson F , Gamo FJ , Gancedo C , Goffeau A , Goulding SE , Grivell LA , Habbig B , Hand NJ , Hani J , Hattenhorst U , Hebling U , Hernando Y , Herrero E , Heumann K , Hiesel R , Hilger F , Hofmann B , Hollenberg CP , Hughes B , Jauniaux JC , Kalogeropoulos A , Katsoulou C , Kordes E , Lafuente MJ , Landt O , Louis EJ , Maarse AC , Madania A , Mannhaupt G , Marck C , Martin RP , Mewes HW , Michaux G , Paces V , Parle-McDermott AG , Pearson BM , Perrin A , Pettersson B , Poch O , Pohl TM , Poirey R , Portetelle D , Pujol A , Purnelle B , Ramezani Rad M , Rechmann S , Schwager C , Schweizer M , Sor F , Sterky F , Tarassov IA , Teodoru C , Tettelin H , Thierry A , Tobiasch E , Tzermia M , Uhlen M , Unseld M , Valens M , Vandenbol M , Vetter I , Vlcek C , Voet M , Volckaert G , Voss H , Wambutt R , Wedler H , Wiemann S , Winsor B , Wolfe KH , Zollner A , Zumstein E , Kleine K
Ref : Nature , 387 :98 , 1997
Abstract : Chromosome XV was one of the last two chromosomes of Saccharomyces cerevisiae to be discovered. It is the third-largest yeast chromosome after chromosomes XII and IV, and is very similar in size to chromosome VII. It alone represents 9% of the yeast genome (8% if ribosomal DNA is included). When systematic sequencing of chromosome XV was started, 93 genes or markers were identified, and most of them were mapped. However, very little else was known about chromosome XV which, in contrast to shorter chromosomes, had not been the object of comprehensive genetic or molecular analysis. It was therefore decided to start sequencing chromosome XV only in the third phase of the European Yeast Genome Sequencing Programme, after experience was gained on chromosomes III, XI and II. The sequence of chromosome XV has been determined from a set of partly overlapping cosmid clones derived from a unique yeast strain, and physically mapped at 3.3-kilobase resolution before sequencing. As well as numerous new open reading frames (ORFs) and genes encoding tRNA or small RNA molecules, the sequence of 1,091,283 base pairs confirms the high proportion of orphan genes and reveals a number of ancestral and successive duplications with other yeast chromosomes.
ESTHER : Dujon_1997_Nature_387_98
PubMedSearch : Dujon_1997_Nature_387_98
PubMedID: 9169874
Gene_locus related to this paper: yeast-FSH3 , yeast-yo059

Title : Crystal structure of a bacterial lipase from Chromobacterium viscosum ATCC 6918 refined at 1.6 angstroms resolution - Lang_1996_J.Mol.Biol_259_704
Author(s) : Lang D , Hofmann B , Haalck L , Hecht HJ , Spener F , Schmid RD
Ref : Journal Molecular Biology , 259 :704 , 1996
Abstract : The crystal structure of a lipase from the bacterium Chromobacterium viscosum ATCC 6918 (CVL) has been determined by isomorphous replacement and refined at 1.6 angstroms resolution to an R-factor of 17.8%. The lipase has the overall topology of an alpha/beta type protein, which was also found for previously determined lipase structures. The catalytic triad of the active center consists of the residues Ser87, Asp263 and His285. These residues are not exposed to the solvent, but a narrow channel connects them with the molecular surface. This conformation is very similar to the previously reported closed conformation of Pseudomonas glumae lipase (PGL), but superposition of the two lipase structures reveals several conformational differences. r.m.s. deviations greater than 2 angstroms are found for the C alpha-atoms of the polypeptide chains from His15 to Asp28, from Leu49 to Ser54 and from Lys128 to Gln158. Compared to the PGL structure in the CVL structure, three alpha-helical fragments are shorter, one beta-strand is longer and an additional antiparallel beta-sheet is found. In contrast to PGL, CVL displays an oxyanion hole, which is stabilized by the amide nitrogen atoms of Leu17 and Gln88, and a cis-peptide bond between Gln291 and Leu292. CVL contains a Ca2+, like the PGL, which is coordinated by four oxygen atoms from the protein and two water molecules.
ESTHER : Lang_1996_J.Mol.Biol_259_704
PubMedSearch : Lang_1996_J.Mol.Biol_259_704
PubMedID: 8683577
Gene_locus related to this paper: burgl-lipas