Time filter

Source Type

Burg bei Magdeburg, Germany

Koch O.,Intervet Innovation GmbH | Koch O.,Molisa GmbH
Molecular Informatics | Year: 2012

Turns are essential for protein structure as they allow the polypeptide chain to fold backup on itself. They also occur within protein binding sites, at protein - protein interfaces and in small bioactive peptides, where they can play a crucial role for molecular recognition. Turn structures are an important class of protein secondary structure, although relatively little attention is paid to them with respect to helices and β-sheets. Protein structure prediction, functional analysis of proteins and peptides, and computer-aided drug design could all benefit from making use of accurately predicted turn structures from amino acid sequence. Here, recent advances of turn structure prediction and the underlying turn classification will be discussed together with their applications. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Horst S.A.,Hannover Medical School | Jaeger T.,Molisa GmbH | Denkel L.A.,Hannover Medical School | Rouf S.F.,Hannover Medical School | And 2 more authors.
Journal of Bacteriology | Year: 2010

At present, Salmonella is considered to express two peroxiredoxin-type peroxidases, TsaA and AhpC. Here we describe an additional peroxiredoxin, Tpx, in Salmonella enterica and show that a single tpx mutant is susceptible to exogenous hydrogen peroxide (H2O2), that it has a reduced capacity to degrade H2O2 compared to the ahpCF and tsaA mutants, and that its growth is affected in activated macrophages. These results suggest that Tpx contributes significantly to the sophisticated defense system that the pathogen has evolved to survive oxidative stress. Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source

Koch O.,MSD Animal Health Innovation GmbH | Koch O.,Molisa GmbH | Koch O.,TU Dortmund | Jager T.,Molisa GmbH | And 9 more authors.
Journal of Medicinal Chemistry | Year: 2013

A virtual screening campaign is presented that led to small molecule inhibitors of thioredoxin reductase of Mycobacterium tuberculosis (MtTrxR) that target the protein-protein interaction site for the substrate thioredoxin (Trx). MtTrxR is a promising drug target because it dominates the Trx-dependent hydroperoxide metabolism and the reduction of ribonucleotides, thus facilitating survival and proliferation of M. tuberculosis. Moreover, MtTrxR sufficiently differs from its human homologs to suggest the possibility of selective inhibition if the MtTrxR-Trx interaction site is targeted. To this end, high-throughput docking of 6.5 million virtual compounds to the thioredoxin binding site of MtTrxR combined with constraints as filtering steps was applied. A total of 170 high-scoring compounds yielded 18 compounds that inhibited MtTrxR with IC50 values up to the low micromolar range, thus revealing that the protein-protein interaction site of MtTrxR is indeed druggable. Most importantly, selectivity toward MtTrxR in comparison to human TrxR (HsTrxR) is also demonstrated. © 2013 American Chemical Society. Source

MacCari G.,University of Siena | Jaeger T.,Molisa GmbH | Moraca F.,University of Siena | Biava M.,University of Rome La Sapienza | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Trypanothione reductase (TryR) is one of the favorite targets for those designing drugs for the treatment of Chagas disease. We present the application of a fast virtual screening approach for designing hit compounds active against TryR. Our protocol combines information derived from structurally known inhibitors and from the TryR receptor structure. Five structurally diverse hit compounds active against TryR and holding promise for the treatment of Chagas disease are reported. © 2011 Elsevier Ltd. All rights reserved. Source

Koch O.,MSD Animal Health Innovation GmbH | Koch O.,Molisa GmbH | Koch O.,TU Dortmund | Cappel D.,University of Wurzburg | And 9 more authors.
PLoS ONE | Year: 2013

The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two Mg2+ ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows N1-glutathionylation of N8-glutathionylspermidine, classifying N8-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for N8-glutathionylspermidine was characterised as druggable. © 2013 Koch et al. Source

Discover hidden collaborations