12 results on '"Gasset, Maria"'
Search Results
2. Predicted α-Helical Regions of the Prion Protein when Synthesized as Peptides Form Amyloid
- Author
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Gasset, Maria, Baldwin, Michael A., Lloyd, David H., Gabriel, Jean-Marc, Holtzman, David M., Cohen, Fred, Fletterick, Robert, and Prusiner, Stanley B.
- Published
- 1992
3. Perturbation of the Secondary Structure of the Scrapie Prion Protein Under Conditions that Alter Infectivity
- Author
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Gasset, Maria, Baldwin, Michael A., Fletterick, Robert J., and Prusiner, Stanley B.
- Published
- 1993
4. Spectroscopic Characterization of Conformational Differences between PrP C and PrP Sc : An α -helix to β -sheet Transition
- Author
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Baldwin, Michael A., Pan, Keh-Ming, Nguyen, Jack, Huang, Ziwei, Groth, Darlene, Serban, Ana, Gasset, Maria, Mehlhorn, Ingrid, Fletterick, Robert J., Cohen, Fred E., and Prusiner, Stanley B.
- Published
- 1994
5. Development of the Fc-III Tagged Protein Expression System for Protein Purification and Detection.
- Author
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Shan Feng, Enbing Tian, Lei Zhang, Qingtao Wang, Haiteng Deng, and Gasset, Maria
- Subjects
PROTEINS ,PEPTIDES ,IMMUNOGLOBULINS ,ESCHERICHIA coli ,BIOCHEMISTRY ,PROTEOMICS - Abstract
In the present work, we developed the Fc-III tagged protein expression system for protein purification and detection. The Fc-III sequence encodes for a 13 residue peptide and this peptide is cyclized by disulfide bond formation when the fusion protein is expressed. The Fc-III-fusion proteins selectively bind to immunoglobulin Fc domains (IgG-Fc) expressed from E. coli. We showed the efficient purification of Fc-III tagged proteins by immobilized non-native IgG- Fc and the detection of the cellular locations of fusion proteins by fluorescent-conjugated IgG-Fc. Our results prove that Fc-III tagged protein expression system is a simple and efficient tool for protein purification and detection and is a useful addition to the biochemistry and proteomics toolbox. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
6. Aptamarker prediction of brain amyloid-β status in cognitively normal individuals at risk for Alzheimer’s disease
- Author
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Penner, G, Lecocq, S, Chopin, A, Vedoya, X, Lista, S, Vergallo, A, Cavedo, E, Lejeune, F, Dubois, B, Hampel, H, Bakardjian, H, Benali, H, Bertin, H, Bonheur, J, Boukadida, L, Boukerrou, N, Chiesa, Pa, Colliot, O, Dubois, M, Epelbaum, S, Gagliardi, G, Genthon, R, Habert, M, Houot, M, Kas, A, Lamari, F, Levy, M, Metzinger, C, Mochel, F, Nyasse, F, Poisson, C, Potier, M, Revillon, M, Santos, A, Andrade, Ks, Sole, M, Surtee, M, de Schotten, Mt, Younsi, N, Afshar, M, Aguilar, Lf, Akman-Anderson, L, Aremas, J, Avila, J, Babiloni, C, Baldacci, F, Batrla, R, Benda, N, Black, Kl, Bokde, Alw, Bonuccelli, U, Broich, K, Cacciola, F, Caraci, F, Caruso, G, Castrillo, J, Ceravolo, R, Corbo, M, Corvol, J, Cuello, Ac, Cummings, Jl, Depypere, H, Duggento, A, Emanuele, E, Escott-Price, V, Federoff, H, Ferretti, Mt, Fiandaca, M, Frank, Ra, Garaci, F, Geerts, H, Giacobini, E, Giorgi, Fs, Goetzl, Ej, Graziani, M, Haberkamp, M, Hanisch, B, Herholz, K, Hernandez, F, Imbimbo, Bp, Kapogiannis, D, Karran, E, Kiddle, Sj, Kim, Sh, Koronyo, Y, Koronyo-Hamaoui, M, Langevin, T, Lehericy, S, Lemercier, P, Llavero, F, Lorenceau, J, Lucia, A, Mango, D, Mapstone, M, Neri, C, Nistico, R, O'Bryant, Se, Palermo, G, Perry, G, Ritchie, C, Rossi, S, Saidi, A, Santarnecchi, E, Schneider, Ls, Sporns, O, Toschi, N, Valenzuela, Pl, Vellas, B, Verdooner, Sr, Villain, N, Giudici, Kv, Watling, M, Welikovitch, La, Woodcock, J, Younesi, E, Zugaza, Jl, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Gasset, Maria
- Subjects
Male ,Aging ,Amyloid β ,MESH: SELEX Aptamer Technique ,[SDV]Life Sciences [q-bio] ,Oligonucleotides ,Artificial Gene Amplification and Extension ,Disease ,Neurodegenerative ,Alzheimer's Disease ,Pathology and Laboratory Medicine ,Biochemistry ,Polymerase Chain Reaction ,Diagnostic Radiology ,Negative selection ,Medical Conditions ,Mathematical and Statistical Techniques ,0302 clinical medicine ,MESH: Aged, 80 and over ,MESH: Early Diagnosis ,80 and over ,Medicine and Health Sciences ,Biomarker discovery ,Tomography ,Aged, 80 and over ,MESH: Aged ,screening and diagnosis ,0303 health sciences ,Multidisciplinary ,Nucleotides ,Mathematical Models ,Radiology and Imaging ,SELEX Aptamer Technique ,Settore MED/37 - Neuroradiologia ,Neurodegenerative Diseases ,MESH: Case-Control Studies ,MESH: Amyloid beta-Peptides ,Detection ,Neurology ,Neurological ,Medicine ,Biomedical Imaging ,Female ,Biotechnology ,4.2 Evaluation of markers and technologies ,Research Article ,Amyloid ,General Science & Technology ,Imaging Techniques ,Science ,Aptamer ,Neuroimaging ,and over ,Computational biology ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,Clinical Research ,Diagnostic Medicine ,Alzheimer Disease ,Mental Health and Psychiatry ,Acquired Cognitive Impairment ,Humans ,Risk factor ,Molecular Biology Techniques ,Molecular Biology ,Aged ,030304 developmental biology ,Amyloid beta-Peptides ,MESH: Humans ,Prevention ,Neurosciences ,Alzheimer Precision Medicine Initiative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Biology and Life Sciences ,Omics ,MESH: Male ,Brain Disorders ,4.1 Discovery and preclinical testing of markers and technologies ,Early Diagnosis ,Case-Control Studies ,MESH: Biomarkers ,Dementia ,INSIGHT-preAD study group ,MESH: Female ,Biomarkers ,Positron Emission Tomography ,030217 neurology & neurosurgery ,MESH: Alzheimer Disease ,Neuroscience - Abstract
International audience; The traditional approach to biomarker discovery for any pathology has been through hypothesis-based research one candidate at a time. The objective of this study was to develop an agnostic approach for the simultaneous screening of plasma for consistent molecular differences between a group of individuals exhibiting a pathology and a group of healthy individuals. To achieve this, we focused on developing a predictive tool based on plasma for the amount of brain amyloid-β deposition as observed in PET scans. The accumulation of brain amyloid-β (Aβ) plaques is a key risk factor for the development of Alzheimer's disease. A contrast was established between cognitively normal individuals above the age of 70 that differed for the amount of brain amyloid-β observed in PET scans (INSIGHT study group). Positive selection was performed against a pool of plasma from individuals with high brain amyloid and negative selection against a pool of plasma from individuals with low brain amyloid This enriched, selected library was then applied to plasma samples from 11 individuals with high levels of brain amyloid and 11 individuals with low levels of brain Aβ accumulation. Each of these individually selected libraries was then characterized by next generation sequencing, and the relative frequency of 10,000 aptamer sequences that were observed in each selection was screened for ability to explain variation in brain amyloid using sparse partial least squares discriminant analysis. From this analysis a subset of 44 aptamers was defined, and the individual aptamers were synthesized. This subset was applied to plasma samples from 70 cognitively normal individuals all above the age of 70 that differed for brain amyloid deposition. 54 individuals were used as a training set, and 15 as a test set. Three of the 15 individuals in the test set were mis-classified resulting in an overall accuracy of 80% with 86% sensitivity and 75% specificity. The aptamers included in the subset serve directly as biomarkers, thus we have named them Aptamarkers. There are two potential applications of these results: extending the predictive capacity of these aptamers across a broader range of individuals, and/or using the individual aptamers to identify targets through covariance analysis and reverse omics approaches. We are currently expanding applications of the Aptamarker platform to other diseases and target matrices.
- Published
- 2021
7. Inter- and Intra-octarepeat Cu(II) Site Geometries in the Prion Protein.
- Author
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Morante, Silvia, González-Iglesias, Reinerio, Potrich, Cristina, Meneghini, Carlo, Meyer-Klaucke, Wolfram, Menestrina, Gianfranco, and Gasset, Maria
- Subjects
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COPPER , *PRIONS , *PROTEIN binding , *BINDING sites , *CYTOCHEMISTRY , *BIOCHEMISTRY - Abstract
Cu(II) binding to the α prion protein (αPrP) can be both intramolecular and intermolecular. X-ray absorption spectroscopy at the copper K-edge has been used to explore the site geometry under each binding mode using both insoluble polymeric Cu(II)-αBoPrP-(24-242) (bovine PrP) complexes and soluble Cu(II) complexes of peptides containing one, two, and four copies of the octarepeat. Analysis of the extended region of the spectra using a multiple scattering approach revealed two types of sites differing in the number of His residues in the first coordination shell of Cu(II). Peptides containing one and two-octarepeat copies in sub-stoichiometric Cu(II) complexes showed the direct binding of a single His in accord with crystallographic intra-repeat geometry. Alternatively, the polymeric Cu(II)-αBoPrP-(24-242) complex and Cu(II) in its soluble complex with a fouroetarepeat peptide at half-site-occupancy showed Cu(II) directly bound to two His residues, consistent with an inter-repeat binding mode. Increasing the Cu(II) site occupancy from 0.5 to 0.75 in the peptide containing four octarepeats resulted in spectral features that are intermediate to those of the inter- and intra-repeat modes. The transition from His-Cu-His (inter-repeat) to Cu-His (intra-repeat) on increasing Cu(II) saturation offers a structural basis for the positive cooperativity of the cation binding process and explains the capacity of αPrP to participate in Cu(II)-mediated intermolecular interactions. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
8. Boronate complex formation with Dopa containing mussel adhesive protein retards ph-induced oxidation and enables adhesion to mica
- Author
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J. Herbert Waite, Yunfei Chen, Jacob N. Israelachvili, Eric Danner, Yajing Kan, and Gasset, Maria
- Subjects
General Science & Technology ,Materials Science ,Biophysics ,lcsh:Medicine ,02 engineering and technology ,010402 general chemistry ,Biochemistry ,Protein Chemistry ,01 natural sciences ,Redox ,Biomaterials ,Acetic acid ,chemistry.chemical_compound ,Adhesives ,Oxidation ,Oxidizing agent ,Polymer chemistry ,Animals ,Post-Translational Modification ,Protein Interactions ,lcsh:Science ,chemistry.chemical_classification ,Multidisciplinary ,Chemistry ,Physics ,lcsh:R ,Chemical Reactions ,Proteins ,Biology and Life Sciences ,Polymer ,Adhesion ,021001 nanoscience & nanotechnology ,Boronic Acids ,Dihydroxyphenylalanine ,0104 chemical sciences ,Amino acid ,Mollusca ,Covalent bond ,Physical Sciences ,Aluminum Silicates ,lcsh:Q ,Structural Proteins ,Adhesive ,0210 nano-technology ,Research Article ,Biotechnology - Abstract
© 2014 Kan et al. The biochemistry of mussel adhesion has inspired the design of surface primers, adhesives, coatings and gels for technological applications. These mussel-inspired systems often focus on incorporating the amino acid 3,4-dihydroxyphenyl-L-alanine (Dopa) or a catecholic analog into a polymer. Unfortunately, effective use of Dopa is compromised by its susceptibility to auto-oxidation at neutral pH. Oxidation can lead to loss of adhesive function and undesired covalent cross-linking. Mussel foot protein 5 (Mfp-5), which contains ∼30 mole % Dopa, is a superb adhesive under reducing conditions but becomes nonadhesive after pH-induced oxidation. Here we report that the bidentate complexation of borate by Dopa to form a catecholato-boronate can be exploited to retard oxidation. Although exposure of Mfp-5 to neutral pH typically oxidizes Dopa, resulting in a
- Published
- 2014
9. Expression and characterization of Drosophila signal peptide peptidase-like (sppL), a gene that encodes an intramembrane protease
- Author
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Brian Biehs, Thomas B. Kornberg, David J. Casso, Songmei Liu, and Gasset, Maria
- Subjects
Enzymologic ,lcsh:Medicine ,Sequence Homology ,Genes, Insect ,Biochemistry ,Animals, Genetically Modified ,0302 clinical medicine ,Complementary ,Catalytic Domain ,Molecular Cell Biology ,Drosophila Proteins ,Aspartic Acid Endopeptidases ,Developmental ,Cloning, Molecular ,lcsh:Science ,Peptide sequence ,Phylogeny ,Regulation of gene expression ,Genetics ,0303 health sciences ,Multidisciplinary ,biology ,Gene Expression Regulation, Developmental ,Amino Acid ,Drosophila melanogaster ,Essential gene ,Signal peptide peptidase ,Drosophila Protein ,Research Article ,Subcellular Fractions ,Biotechnology ,Proteases ,Protein Structure ,DNA, Complementary ,Intramembrane protease ,General Science & Technology ,1.1 Normal biological development and functioning ,Molecular Sequence Data ,Genetically Modified ,Gene Expression Regulation, Enzymologic ,Molecular Genetics ,03 medical and health sciences ,Underpinning research ,Animals ,Humans ,Amino Acid Sequence ,Biology ,030304 developmental biology ,Sequence Homology, Amino Acid ,Base Sequence ,lcsh:R ,Proteins ,Molecular ,DNA ,biology.organism_classification ,Protein Structure, Tertiary ,Gene Expression Regulation ,Genes ,Mutation ,biology.protein ,Unfolded Protein Response ,lcsh:Q ,Generic health relevance ,Insect ,030217 neurology & neurosurgery ,Tertiary ,Developmental Biology ,Cloning - Abstract
Intramembrane proteases of the Signal Peptide Peptidase (SPP) family play important roles in developmental, metabolic and signaling pathways. Although vertebrates have one SPP and four SPP-like (SPPL) genes, we found that insect genomes encode one Spp and one SppL. Characterization of the Drosophila sppL gene revealed that the predicted SppL protein is a highly conserved structural homolog of the vertebrate SPPL3 proteases, with a predicted nine-transmembrane topology, an active site containing aspartyl residues within a transmembrane region, and a carboxy-terminal PAL domain. SppL protein localized to both the Golgi and ER. Whereas spp is an essential gene that is required during early larval stages and whereas spp loss-of-function reduced the unfolded protein response (UPR), sppL loss of function had no apparent phenotype. This was unexpected given that genetic knockdown phenotypes in other organisms suggested significant roles for Spp-related proteases.
- Published
- 2012
10. Oligomerization of ZFYVE27 (Protrudin) Is Necessary to Promote Neurite Extension
- Author
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Anna Sikorska, Ashraf U. Mannan, Marta M. Czyzewska, D. V. Krishna Pantakani, Chiranjeevi Bodda, Gasset, Maria, and Biology
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Cytoplasm ,Anatomy and Physiology ,Vesicular Transport Proteins ,lcsh:Medicine ,Spastin ,Biochemistry ,Polyethylene Glycols ,Motor Neuron Diseases ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Biopolymers ,Molecular Cell Biology ,Neurobiology of Disease and Regeneration ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,Neuronal Morphology ,Peripheral membrane protein ,Neurochemistry ,Neurodegenerative Diseases ,Cellular Structures ,Cell biology ,Neurology ,Medicine ,Research Article ,Subcellular Fractions ,Neurite ,Immunoprecipitation ,Octoxynol ,ZFYVE27 (Protrudin) ,Neurogenesis ,Biology ,spastic paraplegia ,neurite extensions ,Neurological System ,Protein–protein interaction ,03 medical and health sciences ,Tetramer ,Two-Hybrid System Techniques ,Genetics ,Neurites ,Animals ,Phosphatidylinositol ,030304 developmental biology ,lcsh:R ,chemistry ,Cellular Neuroscience ,NIH 3T3 Cells ,lcsh:Q ,Carrier Proteins ,030217 neurology & neurosurgery ,Neuroscience - Abstract
ZFYVE27 (Protrudin) was originally identified as an interacting partner of spastin, which is most frequently mutated in hereditary spastic paraplegia. ZFYVE27 is a novel member of FYVE family, which is implicated in the formation of neurite extensions by promoting directional membrane trafficking in neurons. Now, through a yeast two-hybrid screen, we have identified that ZFYVE27 interacts with itself and the core interaction region resides within the third hydrophobic region (HR3) of the protein. We confirmed the ZFYVE27’s self-interaction in the mammalian cells by co-immunoprecipitation and co-localization studies. To decipher the oligomeric nature of ZFYVE27, we performed sucrose gradient centrifugation and showed that ZFYVE27 oligomerizes into dimer/tetramer forms. Sub-cellular fractionation and Triton X-114 membrane phase separation analysis indicated that ZFYVE27 is a peripheral membrane protein. Furthermore, ZFYVE27 also binds to phosphatidylinositol 3-phosphate lipid moiety. Interestingly, cells expressing ZFYVE27DHR3 failed to produce protrusions instead caused swelling of cell soma. When ZFYVE27DHR3 was co-expressed with wild-type ZFYVE27 (ZFYVE27WT), it exerted a dominant negative effect on ZFYVE27WT as the cells co-expressing both proteins were also unable to induce protrusions and showed cytoplasmic swelling. Altogether, it is evident that a functionally active form of oligomer is crucial for ZFYVE27 ability to promote neurite extensions. peerReviewed
- Published
- 2011
11. A novel metagenomic short-chain dehydrogenase/reductase attenuates Pseudomonas aeruginosa biofilm formation and virulence on Caenorhabditis elegans
- Author
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Hinrich Schulenburg, Wolfgang R. Streit, Hubert Mayerhofer, Patrick Bijtenhoorn, Jochen Müller-Dieckmann, Stephanie Grond, Rolf Daniel, Katja Dierking, Christina Schipper, Andrea Thürmer, Elzbieta Brzuszkiewicz, Matthias Szesny, Christian Utpatel, Claudia Hornung, and Gasset, Maria
- Subjects
Bacterial Diseases ,Reductase ,medicine.disease_cause ,Biochemistry ,chemistry.chemical_compound ,Molecular Cell Biology ,0303 health sciences ,Multidisciplinary ,Virulence ,Enzyme Classes ,Quorum Sensing ,food and beverages ,Animal Models ,Enzymes ,Infectious Diseases ,Quorum Quenching ,biofilm ,bacteria ,Caenorhabditis elegans ,Pseudomonas aeruginosa ,Medicine ,Oxidoreductases ,Research Article ,Signal Transduction ,Science ,Biology ,Microbiology ,Molecular Genetics ,03 medical and health sciences ,Pyocyanin ,Model Organisms ,Bacterial Proteins ,medicine ,Genetics ,Animals ,Gene Regulation ,Pseudomonas Infections ,030304 developmental biology ,030306 microbiology ,Gene Expression Profiling ,Biofilm ,Bacteriology ,biochemical phenomena, metabolism, and nutrition ,Quorum sensing ,chemistry ,Biofilms ,Pyocyanine ,Heterologous expression ,Metagenomics ,Bacterial Biofilms ,NADP - Abstract
In Pseudomonas aeruginosa, the expression of a number of virulence factors, as well as biofilm formation, are controlled by quorum sensing (QS). N-Acylhomoserine lactones (AHLs) are an important class of signaling molecules involved in bacterial QS and in many pathogenic bacteria infection and host colonization are AHL-dependent. The AHL signaling molecules are subject to inactivation mainly by hydrolases (Enzyme Commission class number EC 3) (i.e. N-acyl-homoserine lactonases and N-acyl-homoserine-lactone acylases). Only little is known on quorum quenching mechanisms of oxidoreductases (EC 1). Here we report on the identification and structural characterization of the first NADP-dependent short-chain dehydrogenase/reductase (SDR) involved in inactivation of N-(3-oxo-dodecanoyl)-L-homoserine lactone (3-oxo-C(12)-HSL) and derived from a metagenome library. The corresponding gene was isolated from a soil metagenome and designated bpiB09. Heterologous expression and crystallographic studies established BpiB09 as an NADP-dependent reductase. Although AHLs are probably not the native substrate of this metagenome-derived enzyme, its expression in P. aeruginosa PAO1 resulted in significantly reduced pyocyanin production, decreased motility, poor biofilm formation and absent paralysis of Caenorhabditis elegans. Furthermore, a genome-wide transcriptome study suggested that the level of lasI and rhlI transcription together with 36 well known QS regulated genes was significantly (≥10-fold) affected in P. aeruginosa strains expressing the bpiB09 gene in pBBR1MCS-5. Thus AHL oxidoreductases could be considered as potent tools for the development of quorum quenching strategies.
- Published
- 2011
12. Systematic Exploitation of Multiple Receptor Conformations for Virtual Ligand Screening
- Author
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Giovanni Bottegoni, Ruben Abagyan, Walter Rocchia, Andrea Cavalli, Manuel Rueda, Bottegoni G., Rocchia W., Rueda M., Abgyan R., Cavalli A, and Gasset, Maria
- Subjects
Protein Conformation ,lcsh:Medicine ,Ligands ,Bioinformatics ,Biochemistry ,Computational Chemistry ,Protein structure ,Receptors ,Drug Discovery ,Macromolecular Structure Analysis ,Combinatorial Chemistry Techniques ,Biomacromolecule-Ligand Interactions ,lcsh:Science ,Protocol (object-oriented programming) ,Multidisciplinary ,Drug discovery ,Chemistry ,Physics ,Cell Surface ,Medicine ,Biophysic Al Simulations ,Algorithms ,Research Article ,Biotechnology ,Protein Binding ,Protein Structure ,Drugs and Devices ,Drug Research and Development ,General Science & Technology ,Biophysics ,Receptors, Cell Surface ,Computational biology ,Protein Chemistry ,Chemical Biology ,Humans ,Set (psychology) ,Biology ,Flexibility (engineering) ,Virtual screening ,Ligand ,lcsh:R ,Proteins ,Computational Biology ,Small Molecules ,Drug Design ,lcsh:Q ,Generic health relevance ,Medicinal Chemistry - Abstract
The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic receptor conformations, a powerful way of discretely representing protein plasticity, can be exploited in screening protocols to separate binders from non-binders. Our analyses encompass 36 targets of pharmaceutical relevance and are based on actual molecules with reported activity against those targets. The results suggest that an ensemble receptor-based protocol displays a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart. Moreover, such a protocol can be engineered not only to enrich a higher number of active compounds, but also to enhance their chemical diversity. Finally, some clear indications can be gathered on how to select a subset of receptor conformations that is most likely to provide the best performance in a real life scenario.
- Published
- 2011
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