Christoph A Sotriffer

University of Wuerzburg, Würzburg, Bavaria, Germany

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Publications (70)242.13 Total impact

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    ABSTRACT: Selective and nanomolar acetylcholinesterase inhibitors were obtained by connecting tri- and tetracyclic quinazolinones-previously described as moderately active and unselective cholinesterase (ChE) inhibitors-via a hydroxyl group in para position to an anilinic nitrogen with different amines linked via a three carbon atom spacer. These tri- and tetracyclic quinazolinones containing different alicyclic ring sizes and connected to tertiary amines were docked to a high-resolution hAChE crystal structure to investigate the preferred binding mode in relation to results obtained by experimental structure-activity relationships. While the 'classical orientation' locating the heterocycle in the active site was rarely found, an alternative binding mode with the basic aliphatic amine in the active center ('inverted' orientation) was obtained for most compounds. Analyses of extended SARs based on this inverted binding mode are able to explain the compounds' binding affinities at AChE.
    Bioorganic & medicinal chemistry. 07/2014;
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    ABSTRACT: Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549 - a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-ACP reductase (FabI) - has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections (www.crystalgenomics.com), which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors including CG400549. Based on these structures we rationalize the 65-fold reduced affinity of CG400549 towards Escherichia coli vs. S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms.
    Journal of Biological Chemistry 04/2014; · 4.65 Impact Factor
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    ABSTRACT: Photochromic cholinesterase inhibitors were obtained from cis-1,2-α-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved "photoswitchable". The AChE-induced β-amyloid (Aβ) aggregation assay gave further experimental support to this finding: Aβ1-40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ring-open and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ring-closed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays.
    ACS Chemical Neuroscience 03/2014; · 3.87 Impact Factor
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    ABSTRACT: Combination of AChE inhibiting and histamine H3 receptor antagonizing properties in a single molecule might show synergistic effects to improve cognitive deficits in Alzheimer's disease, since both pharmacological actions are able to enhance cholinergic neurotransmission in the cortex. However, whereas AChE inhibitors prevent hydrolysis of acetylcholine also peripherally, histamine H3 antagonists will raise acetylcholine levels mostly in the brain due to predominant occurrence of the receptor in the central nervous system. In this work, we designed and synthesized two novel classes of tri- and tetracyclic nitrogen-bridgehead compounds acting as dual AChE inhibitors and histamine H3 antagonists by combining the nitrogen-bridgehead moiety of novel AChE inhibitors with a second N-basic fragment based on the piperidinylpropoxy pharmacophore with different spacer lengths. Intensive structure-activity relationships (SARs) with regard to both biological targets led to compound 41 which showed balanced affinities as hAChE inhibitor with IC50 = 33.9 nM, and hH3R antagonism with Ki = 76.2 nM with greater than 200-fold selectivity over the other histamine receptor subtypes. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds and molecular dynamics studies to explain high affinity at the hH3R.
    ACS Chemical Neuroscience 01/2014; · 3.87 Impact Factor
  • David Zilian, Christoph A Sotriffer
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    ABSTRACT: A major shortcoming of empirical scoring functions for protein-ligand complexes is the low degree of correlation between predicted and experimental binding affinities, as frequently observed not only for large and diverse datasets, but also for SAR series of particular targets. Improvements can be envisaged by developing new descriptors, by employing larger training sets of higher quality, and by resorting to more sophisticated regression methods. Herein, we describe the use of SFCscore descriptors to develop an improved scoring function by means of a PDBbind training set of 1005 complexes in combination with Random Forest for regression. This provided SFCscore(RF) as a new scoring function with significantly improved performance on the PDBbind and CSAR-NRC HiQ benchmarks in comparison to previously developed SFCscore functions. A leave-cluster-out cross validation and the performance in the CSAR 2012 scoring exercise point out remaining limitations, but also directions for further improvement of SFCscore(RF) in particular and empirical scoring functions in general.
    Journal of Chemical Information and Modeling 05/2013; · 4.30 Impact Factor
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    ABSTRACT: Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI) - an important target for the development of new anti-staphylococcal drugs - as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Due to its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 hours. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme.
    Biochemistry 05/2013; · 3.38 Impact Factor
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    ABSTRACT: Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC50 = 90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 05/2013; · 2.61 Impact Factor
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    ABSTRACT: Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer's disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with IC values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.
    International Journal of Molecular Sciences 01/2013; 14(3):5608-32. · 2.46 Impact Factor
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    ABSTRACT: 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 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 Mg 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 N-glutathionylation of N-glutathionylspermidine, classifying N-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for N-glutathionylspermidine was characterised as druggable.
    PLoS ONE 01/2013; 8(2):e56788. · 3.53 Impact Factor
  • Benjamin Merget, David Zilian, Tobias Müller, Christoph A. Sotriffer
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    ABSTRACT: Motivation: With >8 million new cases in 2010, particularly documented in developing countries, tuberculosis (TB) is still a highly present pandemic and often terminal. This is also due to the emergence of antibiotic-resistant strains (MDR-TB and XDR-TB) of the primary causative TB agent Mycobacterium tuberculosis (MTB). Efforts to develop new effective drugs against MTB are restrained by the unique and largely impermeable composition of the mycobacterial cell wall. Results: Based on a database of antimycobacterial substances (CDD TB), 3815 compounds were classified as active and thus permeable. A data mining approach was conducted to gather the physico-chemical similarities of these substances and delimit them from a generic dataset of drug-like molecules. On the basis of the differences in these datasets, a regression model was generated and implemented into the online tool MycPermCheck to predict the permeability probability of small organic compounds. Discussion: Given the current lack of precise molecular criteria determining mycobacterial permeability, MycPermCheck represents an unprecedented prediction tool intended to support antimycobacterial drug discovery. It follows a novel knowledge-driven approach to estimate the permeability probability of small organic compounds. As such, MycPermCheck can be used intuitively as an additional selection criterion for potential new inhibitors against MTB. Based on the validation results, its performance is expected to be of high practical value for virtual screening purposes. Availability: The online tool is freely accessible under the URL http://www.mycpermcheck.aksotriffer.pharmazie.uni-wuerzburg.de Contact: sotriffer@uni-wuerzburg.de Supplementary information:Supplementary data are available at Bioinformatics online.
    Bioinformatics. 01/2013; 29(1):62-68.
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    Benjamin Merget, David Zilian, Tobias Müller, Christoph A Sotriffer
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    ABSTRACT: MOTIVATION: With over 8 million new cases in 2010, particularly documented in developing countries, tuberculosis (TB) is still a highly present pandemic and often terminal. This is also due to the emergence of antibiotic-resistant strains (MDR-TB and XDR-TB) of the primary causative TB agent Mycobacterium tuberculosis (MTB). Efforts to develop new effective drugs against MTB are restrained by the unique and largely impermeable composition of the mycobacterial cell wall. RESULTS: Based on a database of antimycobacterial substances (CDD TB) 3,815 compounds were classified as active and thus permeable. A data mining approach was conducted to gather the physico-chemical similarities of these substances and delimit them from a generic dataset of drug-like molecules. On the basis of the differences in these datasets, a regression model was generated and implemented into the online tool MycPermCheck to predict the permeability probability of small organic compounds.Discussion: Given the current lack of precise molecular criteria determining mycobacterial permeability, MycPermCheck represents an unprecedented prediction tool intended to support antimycobacterial drug discovery. It follows a novel knowledge-driven approach to estimate the permeability probability of small organic compounds. As such, MycPermCheck can be used intuitively as an additional selection criterion for potential new inhibitors against Mycobacterium tuberculosis. Based on the validation results, its performance is expected to be of high practical value for virtual screening purposes. AVAILABILITY: The online tool is freely accessible under the URL http://www.mycpermcheck.aksotriffer.pharmazie.uni-wuerzburg.de CONTACT: sotriffer@uni-wuerzburg.de.
    Bioinformatics 10/2012; · 5.47 Impact Factor
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    ABSTRACT: The recently discovered FabV enoyl-ACP reductase, which catalyzes the last step of the bacterial fatty acid biosynthesis (FAS-II) pathway, is a promising but unexploited drug target against the reemerging pathogen Yersinia pestis. The structure of Y. pestis FabV in complex with its cofactor reveals that the enzyme features the common architecture of the short-chain dehydrogenase reductase superfamily, but contains additional structural elements that are mostly folded around the usually flexible substrate-binding loop, thereby stabilizing it in a very tight conformation that seals the active site. The structures of FabV in complex with NADH and two newly developed 2-pyridone inhibitors provide insights for the development of new lead compounds, and suggest a mechanism by which the substrate-binding loop opens to admit the inhibitor, a motion that could also be coupled to the interaction of FabV with the acyl-carrier protein substrate.
    Structure 01/2012; 20(1):89-100. · 5.99 Impact Factor
  • Benjamin Schaefer, Caroline Kisker, Christoph A Sotriffer
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    ABSTRACT: Inhibition of the production of fatty acids as essential components of the mycobacterial cell wall has been an established way of fighting tuberculosis for decades. However, increasing resistances and an outdated medical treatment call for the validation of new targets involved in this crucial pathway. In this regard, the β-ketoacyl ACP synthase KasA is a promising enzyme. In this study, three molecular dynamics simulations based on the wildtype crystal structures of inhibitor bound and unbound KasA were performed in order to investigate the flexibility and conformational space of this target. We present an exhaustive analysis of the binding-site flexibility and representative pocket conformations that may serve as new starting points for structure-based drug design. We also revealed a mechanism which may account for the comparatively low binding affinity of thiolactomycin. Furthermore, we examined the behavior of water molecules within the binding pocket and provide recommendations how to handle them in the drug design process. Finally, we analyzed the dynamics of a channel that accommodates the long-chain fatty acid substrates and, thereby, propose a mechanism of substrate access to this channel and how products are most likely released.
    Journal of Computer-Aided Molecular Design 11/2011; 25(11):1053-69. · 3.17 Impact Factor
  • Daniel Cappel, Rickard Wahlström, Ruth Brenk, Christoph A Sotriffer
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    ABSTRACT: The model binding site of the cytochrome c peroxidase (CCP) W191G mutant is used to investigate the structural and dynamic properties of the water network at the buried cavity using computational methods supported by crystallographic analysis. In particular, the differences of the hydration pattern between the uncomplexed state and various complexed forms are analyzed as well as the differences between five complexes of CCP W191G with structurally closely related ligands. The ability of docking programs to correctly handle the water molecules in these systems is studied in detail. It is found that fully automated prediction of water replacement or retention upon docking works well if some additional preselection is carried out but not necessarily if the entire water network in the cavity is used as input. On the other hand, molecular interaction fields for water calculated from static crystal structures and hydration density maps obtained from molecular dynamics simulations agree very well with crystallographically observed water positions. For one complex, the docking and MD results sensitively depend on the quality of the starting structure, and agreement is obtained only after redetermination of the crystal structure and refinement at higher resolution.
    Journal of Chemical Information and Modeling 09/2011; 51(10):2581-94. · 4.30 Impact Factor
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    ABSTRACT: The protozoan parasites of the genus Trypanosoma sp. and Leishmania sp. are responsible for neglected diseases like Chagas’ disease, African sleeping sickness or Leishmaniasis. The trypanothione synthetase (TryS) is an attractive new drug target for the development of trypanocidal and antileishmanial drugs [1]. In our virtual screening campaign for targeting the trypanothione synthetase (TryS) we used representative protein conformations derived from a computational analysis using molecular dynamics (MD) simulations of this key component of trypanothione biosynthesis. The publicly available crystal structure lacks a variable loop region that is known to be important for trypanothione biosynthesis. MD simulations turned out to be a good tool to model this loop region and obtain a more complete set of protein conformations for subsequent use in virtual screening [2]. For creating a structure-based consensus pharmacophore model, Superstar [3] was deployed to generate favourable non-bonded interaction maps of different functional groups (probes) for all representative protein conformations. The pharmacophore model was then created for the rigid part of the binding pocket based on high- propensity peaks of these maps. The variable loop region was left out since it can not be depicted by this approach. To include also multiple conformations of the variable loop region, the new ensemble docking feature of Gold was used [4]. After a pharmacophore search within the ZINC database the retrieved molecules were simultaneously docked to the different protein conformations to identify the best combination of ligand pose and protein conformer. Finally, several high-scoring molecules were selected for further testing. We will discuss in detail this combined pharmacophore/ensemble docking approach based on MD simulations and will present the results of the compound selection for testing.
    Journal of Cheminformatics 01/2011; 3:1-1. · 3.59 Impact Factor
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    ABSTRACT: The macrophage infectivity potentiator (MIP) protein is a major virulence factor of Legionella pneumophila, the causative agent of Legionnaires' disease. MIP belongs to the FK506-binding proteins (FKBP) and is necessary for optimal intracellular survival and lung tissue dissemination of L. pneumophila. We aimed to identify new small-molecule inhibitors of MIP by starting from known FKBP12 ligands. Computational analysis, synthesis, and biological testing of pipecolic acid derivatives revealed a promising scaffold for new MIP inhibitors.
    Journal of Medicinal Chemistry 12/2010; 54(1):277-83. · 5.61 Impact Factor
  • Christoph A Sotriffer
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    ABSTRACT: Proteins can undergo a variety of conformational changes upon ligand binding. Although different mechanisms may play a role, the phenomenon is commonly referred to as induced fit to indicate that the tight structural complementarity of the interaction partners is a consequence of the binding event. Docking methods need to take into account this ability of the ligand and the protein to mutually adapt to each other when forming a complex. Handling the ligand as flexible is already common practice in docking applications. This is not yet the case for the protein. In fact, the accurate prediction of protein conformational changes upon ligand binding is still a major challenge, even more if computational speed is an issue, as for example in virtual screening applications. However, significant progress has been made over the past years and many valuable approaches have become available to address the protein flexibility problem and to provide more reliable docking predictions for complexes governed by significant induced-fit effects. This review provides a brief overview of the current situation, the most recent advances, and the remaining limitations of flexible protein docking, with particular focus on approaches handling protein flexibility simultaneously with ligand placement in the docking process.
    Current topics in medicinal chemistry 11/2010; 11(2):179-91. · 4.47 Impact Factor
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    ABSTRACT: Plasmepsins II (EC number: 3.4.23.39) and IV (EC number: 3.4.23.B14) are aspartic proteases present in the food vacuole of the malaria parasite Plasmodium falciparum and are involved in host hemoglobin degradation. A series of pyrrolidine derivatives, originally synthesized as HIV-1 protease inhibitors, were tested for activity against plasmepsin (Plm). Inhibitors in the nanomolar range were discovered for the Plm II and IV isoforms. Detailed studies were carried out to identify putative binding modes that help to explain the underlying structure-activity relationships. Reasonable binding modes were generated for pyrrolidine-3,4-diester derivatives and a substituted 3,4-diaminopyrrolidine inhibitor by using a crystal structure of inhibitor-bound Plm II (PDB ID: 1LEE). Modeling studies indicated that the flap of available Plm crystal structures is not sufficiently opened to accommodate the 3,4-bis(aminomethylene)pyrrolidines. Molecular dynamics simulations were performed to analyze the flexibility of the protein in greater detail, leading to a binding mode hypothesis for the 3,4-bis(aminomethylene)pyrrolidines and providing further insight and general implications for the design of Plm II inhibitors.
    ChemMedChem 03/2010; 5(3):443-54. · 2.84 Impact Factor
  • Martin Sippel, Christoph A Sotriffer
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    ABSTRACT: HIV-1 integrase (IN) is a validated target of anti-AIDS research. The classical approach of designing active-site directed ligands has largely been exploited. A promising alternative strategy to inactivate the enzyme is to prevent the formation of IN dimers. The rational design of dimerization inhibitors, however, is hampered by the lack of relevant structural data about the targeted monomeric form. Therefore, we performed molecular dynamics simulations and subsequent analyses to gain insight into the structural features of the IN catalytic-core-domain dimerization interface. As a result, the formation of a groove and a cavity along the dimerization interface of the IN monomer could be revealed. Both were shown to be suited for accommodating an inhibitory peptide. The results form a valuable basis for the design of ligands targeting the dimerization interface and, thus, of a whole new class of HIV-1 integrase inhibitors.
    Journal of Chemical Information and Modeling 03/2010; 50(4):604-14. · 4.30 Impact Factor
  • Michael Hein, David Zilian, Christoph A. Sotriffer
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    ABSTRACT: Structure-based virtual screening generally relies on three-dimensional pharmacophore methods or docking approaches, which are applied either separately or in combination in screening campaigns. Detection of the best candidates among the compounds that match a pharmacophore model or fit into a binding pocket constitutes the main challenge. Awareness of the advantages and limitations of the different approaches is essential for their successful application in virtual screening.
    Drug Discovery Today Technologies 01/2010; 7(4).

Publication Stats

960 Citations
242.13 Total Impact Points

Institutions

  • 2008–2014
    • University of Wuerzburg
      • Institute of Pharmacy and Food Chemistry
      Würzburg, Bavaria, Germany
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      Erlangen, Bavaria, Germany
  • 2002–2010
    • Philipps-Universität Marburg
      • Institut für Pharmazeutische Chemie
      Marburg an der Lahn, Hesse, Germany
  • 1996–2006
    • University of Innsbruck
      • Institute of General, Inorganic and Theoretical Chemistry
      Innsbruck, Tyrol, Austria
  • 2000–2004
    • Howard Hughes Medical Institute
      Maryland, United States