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Elke Michalsky

Publications and source records attributed to Elke Michalsky.

7 recordsLinked to original sources
PubMed2006

Characterization of GD2 peptide mimotope DNA vaccines effective against spontaneous neuroblastoma metastases.

Disialoganglioside GD2 is an established target for immunotherapy in neuroblastoma. We tested the hypothesis that active immunization against the glycolipid GD2 using DNA vaccines encoding for cyclic GD2-mimicking decapeptides (i.e., GD2 mimotopes) is effective against neuroblastoma. For this purpose, two GD2 peptide mimotopes (MA and MD) were selected based on docking experiments to anti-GD2 antibody ch14.18 (binding free energy: -41.23 kJ/mol for MA and -48.06 kJ/mol for MD) and Biacore analysis (K(d) = 12.3 x 10(-5) mol/L for MA and 5.3 x 10(-5) mol/L for MD), showing a higher affinity of MD over MA. These sequences were selected for DNA vaccine design based on pSecTag2-A (pSA) also including a T-cell helper epitope. GD2 mimicry was shown following transfection of CHO-1 cells with pSA-MA and pSA-MD DNA vaccines, with twice-higher signal intensity for cells expressing MD over MA. Finally, these DNA vaccines were tested for induction of tumor protective immunity in a syngeneic neuroblastoma model following oral DNA vaccine delivery with attenuated Salmonella typhimurium (SL 7207). Only mice receiving the DNA vaccines revealed a reduction of spontaneous liver metastases. The highest anti-GD2 humoral immune response and natural killer cell activation was observed in mice immunized with the pSA-MD, a finding consistent with superior calculated binding free energy, dissociation constant, and GD2 mimicry potential for GD2 mimotope MD over MA. In summary, we show that DNA immunization with pSA-MD may provide a useful strategy for active immunization against neuroblastoma.

Animals↗
PubMed2006

Representation of target-bound drugs by computed conformers: implications for conformational libraries.

BACKGROUND: The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods. RESULTS: Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space. Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space.A number of up to 100 conformers per drug enabled us to reproduce the bound states within a similarity threshold of 1.0 angstroms in 70% of all cases. This fraction rises to about 90% for smaller or average sized drugs. CONCLUSION: Single drugs adopt multiple bioactive conformations if they interact with different target proteins. Due to the structural diversity of binding sites they adopt conformations that are distributed over a broad conformational space and wide energy range. Since the majority of drugs is well represented by a predefined low number of conformers (up to 100) this procedure is a valuable method to compare compounds by three-dimensional features or for fast similarity searches starting with pharmacophores. The underlying 9600 generated drug conformers are downloadable from the Super Drug Web site 1. All superpositions are visualised at the same source. Additional conformers (110,000) of 2400 classified WHO-drugs are also available.

Amino Acid Sequence↗
PubMed2006

SuperMimic--fitting peptide mimetics into protein structures.

BACKGROUND: Various experimental techniques yield peptides that are biologically active but have unfavourable pharmacological properties. The design of structurally similar organic compounds, i.e. peptide mimetics, is a challenging field in medicinal chemistry. RESULTS: SuperMimic identifies compounds that mimic parts of a protein, or positions in proteins that are suitable for inserting mimetics. The application provides libraries that contain peptidomimetic building blocks on the one hand and protein structures on the other. The search for promising peptidomimetic linkers for a given peptide is based on the superposition of the peptide with several conformers of the mimetic. New synthetic elements or proteins can be imported and used for searching. CONCLUSION: We present a graphical user interface for finding peptide mimetics that can be inserted into a protein or for fitting small molecules into a protein. Using SuperMimic, promising locations in proteins for the insertion of mimetics can be found quickly and conveniently.

Algorithms↗
PubMed2005

How well are protein structures annotated in secondary databases?

We investigated to what extent Protein Data Bank (PDB) entries are annotated with second-party information based on existing cross-references between PDB and 15 other databases. We report 2 interesting findings. First, there is a clear "annotation gap" for structures less than 7 years old for secondary databases that are manually curated. Second, the examined databases overlap with each other quite well, dividing the PDB into 2 well-annotated thirds and one poorly annotated third. Both observations should be taken into account in any study depending on the selection of protein structures by their annotation.

Amino Acid Sequence↗
PubMed2005

SuperLigands - a database of ligand structures derived from the Protein Data Bank.

BACKGROUND: Currently, the PDB contains approximately 29,000 protein structures comprising over 70,000 experimentally determined three-dimensional structures of over 5,000 different low molecular weight compounds. Information about these PDB ligands can be very helpful in the field of molecular modelling and prediction, particularly for the prediction of protein binding sites and function. DESCRIPTION: Here we present an Internet accessible database delivering PDB ligands in the MDL Mol file format which, in contrast to the PDB format, includes information about bond types. Structural similarity of the compounds can be detected by calculation of Tanimoto coefficients and by three-dimensional superposition. Topological similarity of PDB ligands to known drugs can be assessed via Tanimoto coefficients. CONCLUSION: SuperLigands supplements the set of existing resources of information about small molecules bound to PDB structures. Allowing for three-dimensional comparison of the compounds as a novel feature, this database represents a valuable means of analysis and prediction in the field of biological and medical research.

Animals↗
PubMed2003

KISS for STRAP: user extensions for a protein alignment editor.

SUMMARY: The Structural Alignment Program STRAP is a comfortable comprehensive editor and analyzing tool for protein alignments. A wide range of functions related to protein sequences and protein structures are accessible with an intuitive graphical interface. Recent features include mapping of mutations and polymorphisms onto structures and production of high quality figures for publication. Here we address the general problem of multi-purpose program packages to keep up with the rapid development of bioinformatical methods and the demand for specific program functions. STRAP was remade implementing a novel design which aims at Keeping Interfaces in STRAP Simple (KISS). KISS renders STRAP extendable to bio-scientists as well as to bio-informaticians. Scientists with basic computer skills are capable of implementing statistical methods or embedding existing bioinformatical tools in STRAP themselves. For bio-informaticians STRAP may serve as an environment for rapid prototyping and testing of complex algorithms such as automatic alignment algorithms or phylogenetic methods. Further, STRAP can be applied as an interactive web applet to present data related to a particular protein family and as a teaching tool. REQUIREMENTS: JAVA-1.4 or higher. AVAILABILITY: http://www.charite.de/bioinf/strap/

Computer Graphics↗