5 results on '"Marouane Ben Jelloul"'
Search Results
2. Identify drug repurposing candidates by mining the Protein Data Bank
- Author
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Laetitia Chanas-Martin, François Delfaud, Stewart A. Adcock, Marouane Ben Jelloul, Stéphane Richard, Fabrice Moriaud, and Jean-Sébastien Surgand
- Subjects
Protein structure database ,Biotin carboxylase ,Binding Sites ,Protein Conformation ,Drug discovery ,Computer science ,Drug Repositioning ,Druggability ,Protein Data Bank (RCSB PDB) ,Proteins ,Computational biology ,computer.file_format ,Protein Data Bank ,Bioinformatics ,Structure-Activity Relationship ,Protein structure ,Pharmaceutical Preparations ,Drug Discovery ,Data Mining ,Databases, Protein ,Molecular Biology ,computer ,Repurposing ,Information Systems - Abstract
Predicting off-targets by computational methods is gaining increasing interest in early-stage drug discovery. Here, we present a computational method based on full 3D comparisons of 3D structures. When a similar binding site is detected in the Protein Data Bank (PDB) (or any protein structure database), it is possible that the corresponding ligand also binds to that similar site. On one hand, this target hopping case is probably rare because it requires a high similarity between the binding sites. On the other hand, it could be a strong rational evidence to highlight possible off-target reactions and possibly a potential undesired side effect. This target-based drug repurposing can be extended a significant step further with the capability of searching the full surface of all proteins in the PDB, and therefore not relying on pocket detection. Using this approach, we describe how MED-SuMo reproduces the repurposing of tadalafil from PDE5A to PDE4A and a structure of PDE4A with tadalafil. Searching for local protein similarities generates more hits than for whole binding site similarities and therefore fragment repurposing is more likely to occur than for drug-sized compounds. In this work, we illustrate that by mining the PDB for proteins sharing similarities with the hinge region of protein kinases. The experimentally validated examples, biotin carboxylase and synapsin, are retrieved. Further to fragment repurposing, this approach can be applied to the detection of druggable sites from 3D structures. This is illustrated with detection of the protein kinase hinge motif in the HIV-RT non-nucleosidic allosteric site.
- Published
- 2011
3. Towards complete validated models in the next generation ofARP/wARP
- Author
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Francisco J. Fernandez, Marouane Ben Jelloul, Richard J. Morris, Serge X. Cohen, Venkataraman Parthasarathy, Gerard J. Kleywegt, Anastassis Perrakis, Mattheos Kakaris, Victor S. Lamzin, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, European Molecular Biology Laboratory [Hamburg] (EMBL), Department of Cell and Molecular Biology [Uppsala], and Uppsala University
- Subjects
Models, Molecular ,Databases, Factual ,Protein Conformation ,Computer science ,Process (engineering) ,media_common.quotation_subject ,Crystallography, X-Ray ,computer.software_genre ,Bioinformatics ,Decision Support Techniques ,03 medical and health sciences ,Structural Biology ,Quality (business) ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Statistical hypothesis testing ,media_common ,Internet ,0303 health sciences ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,business.industry ,030302 biochemistry & molecular biology ,Reproducibility of Results ,Water ,[INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV] ,General Medicine ,Expert system ,Control system ,Software engineering ,business ,computer ,Algorithms ,Software - Abstract
The design of a new versatile control system that will underlie future releases of the automated model-building package ARP/wARP is presented. A sophisticated expert system is under development that will transform ARP/wARP from a very useful model-building aid to a truly automated package capable of delivering complete, well refined and validated models comparable in quality to the result of intensive manual checking, rebuilding, hypothesis testing, refinement and validation cycles of an experienced crystallographer. In addition to the presentation of this control system, recent advances, ideas and future plans for improving the current model-building algorithms, especially for completing partially built models, are presented. Furthermore, a concept for integrating validation routines into the iterative model-building process is also presented.
- Published
- 2004
4. ARP/wARP and molecular replacement: the next generation
- Author
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Fei Long, Alexei A. Vagin, Victor S. Lamzin, Puck Knipscheer, Garib N. Murshudov, Marouane Ben Jelloul, Anastassis Perrakis, Titia K. Sixma, Serge X. Cohen, Joyce H.G. Lebbink, Molecular Genetics, Radiotherapy, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Department of Chemistry [York, UK], University of York [York, UK], and European Molecular Biology Laboratory [Hamburg] (EMBL)
- Subjects
Models, Molecular ,Crystallography, X-Ray ,03 medical and health sciences ,Software ,Atom (programming language) ,Structural Biology ,Quantum mechanics ,refinement ,Databases, Protein ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Physics ,Structure (mathematical logic) ,Protocol (science) ,0303 health sciences ,Iterative and incremental development ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,business.industry ,030302 biochemistry & molecular biology ,model building ,Estimator ,[INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV] ,Proteins ,General Medicine ,Research Papers ,molecular replacement ,Control system ,Ubiquitin-Conjugating Enzymes ,business ,Algorithm ,Model building ,Algorithms - Abstract
A systematic test shows how ARP/wARP deals with automated model building for structures that have been solved by molecular replacement. A description of protocols in the flex-wARP control system and studies of two specific cases are also presented., Automatic iterative model (re-)building, as implemented in ARP/wARP and its new control system flex-wARP, is particularly well suited to follow structure solution by molecular replacement. More than 100 molecular-replacement solutions automatically solved by the BALBES software were submitted to three standard protocols in flex-wARP and the results were compared with final models from the PDB. Standard metrics were gathered in a systematic way and enabled the drawing of statistical conclusions on the advantages of each protocol. Based on this analysis, an empirical estimator was proposed that predicts how good the final model produced by flex-wARP is likely to be based on the experimental data and the quality of the molecular-replacement solution. To introduce the differences between the three flex-wARP protocols (keeping the complete search model, converting it to atomic coordinates but ignoring atom identities or using the electron-density map calculated from the molecular-replacement solution), two examples are also discussed in detail, focusing on the evolution of the models during iterative rebuilding. This highlights the diversity of paths that the flex-wARP control system can employ to reach a nearly complete and accurate model while actually starting from the same initial information.
- Published
- 2007
5. Co-expression of protein complexes in prokaryotic and eukaryotic hosts: experimental procedures, database tracking and case studies
- Author
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Arnaud Poterszman, Didier Busso, Natacha Rochel, Christophe Romier, Dino Moras, Valeria De Marco, Puck Knipscheer, Tamar Unger, Anastassis Perrakis, Titia K. Sixma, Gretel Buchwald, Evangelos Christodoulou, Marouane Ben Jelloul, Valerie Notenboom, Serge X. Cohen, Joyce H.G. Lebbink, Joel L. Sussman, Patrick H.N. Celie, Shira Albeck, Suzan van Gerwen, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radiotherapy, and Molecular Genetics
- Subjects
Insecta ,DNA Repair ,Information Management ,Receptors, Cytoplasmic and Nuclear ,computer.software_genre ,medicine.disease_cause ,MESH: Eukaryotic Cells ,MESH: Recombinant Proteins ,MESH: Insects ,Structural Biology ,MESH: Genetic Vectors ,Databases, Genetic ,MESH: Animals ,MESH: Databases, Genetic ,SPINE (molecular biology) ,MESH: DNA Repair ,0303 health sciences ,Database ,MESH: Escherichia coli ,030302 biochemistry & molecular biology ,MESH: Transcription Factor TFIID ,General Medicine ,Cyclin-Dependent Kinases ,Recombinant Proteins ,Eukaryotic Cells ,MESH: Cyclin-Dependent Kinases ,Macromolecular Complexes ,MESH: Information Management ,Algorithms ,Ubiquitin-Protein Ligases ,Genetic Vectors ,MESH: Computer Security ,MESH: Algorithms ,Biology ,MESH: Receptors, Cytoplasmic and Nuclear ,03 medical and health sciences ,MESH: Computer Simulation ,MESH: RNA ,Structural proteomics ,medicine ,Escherichia coli ,Animals ,Computer Simulation ,Computer Security ,030304 developmental biology ,MESH: Prokaryotic Cells ,Insect cell ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Expression (computer science) ,MESH: Ubiquitin-Protein Ligases ,Prokaryotic Cells ,RNA ,Transcription Factor TFIID ,computer ,Cyclin-Dependent Kinase-Activating Kinase - Abstract
Structure determination and functional characterization of macromolecular complexes requires the purification of the different subunits in large quantities and their assembly into a functional entity. Although isolation and structure determination of endogenous complexes has been reported, much progress has to be made to make this technology easily accessible. Co-expression of subunits within hosts such as Escherichia coli and insect cells has become more and more amenable, even at the level of high-throughput projects. As part of SPINE (Structural Proteomics In Europe), several laboratories have investigated the use co-expression techniques for their projects, trying to extend from the common binary expression to the more complicated multi-expression systems. A new system for multi-expression in E. coli and a database system dedicated to handle co-expression data are described. Results are also reported from various case studies investigating different methods for performing co-expression in E. coli and insect cells.
- Published
- 2006
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