Expanding the Druggable Space of the LSD1/CoREST Epigenetic Target: New Potential Binding Regions for Drug-Like Molecules, Peptides, Protein Partners, and Chromatin
Publication Date
July 18, 2013
Journal
PLOS Computational Biology
Authors
James C. Robertson, Nate C. Hurley, Marcello Tortorici, Giuseppe Ciossani, et al
Volume
9
Issue
7
Pages
e1003158
DOI
http://doi.org/10.1371/journal.pcbi.1003158
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1003158
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23874194
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715402
Europe PMC
http://europepmc.org/abstract/MED/23874194
Web of Science
000322320200046
Scopus
84880773423
Mendeley
http://www.mendeley.com/research/expanding-druggable-space-lsd1corest-epigenetic-target-new-potential-binding-regions-druglike-molecu
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Mendeley | Further Information

{"title"=>"Expanding the Druggable Space of the LSD1/CoREST Epigenetic Target: New Potential Binding Regions for Drug-Like Molecules, Peptides, Protein Partners, and Chromatin", "type"=>"journal", "authors"=>[{"first_name"=>"James C.", "last_name"=>"Robertson", "scopus_author_id"=>"54884181500"}, {"first_name"=>"Nate C.", "last_name"=>"Hurley", "scopus_author_id"=>"55805862700"}, {"first_name"=>"Marcello", "last_name"=>"Tortorici", "scopus_author_id"=>"36437627600"}, {"first_name"=>"Giuseppe", "last_name"=>"Ciossani", "scopus_author_id"=>"27567498800"}, {"first_name"=>"Maria Teresa", "last_name"=>"Borrello", "scopus_author_id"=>"55003299000"}, {"first_name"=>"Nadeem A.", "last_name"=>"Vellore", "scopus_author_id"=>"22981995800"}, {"first_name"=>"A.", "last_name"=>"Ganesan", "scopus_author_id"=>"7006223453"}, {"first_name"=>"Andrea", "last_name"=>"Mattevi", "scopus_author_id"=>"7005232911"}, {"first_name"=>"Riccardo", "last_name"=>"Baron", "scopus_author_id"=>"7202712767"}], "year"=>2013, "source"=>"PLoS Computational Biology", "identifiers"=>{"pui"=>"369438578", "isbn"=>"1553-7358 (Electronic)\\r1553-734X (Linking)", "issn"=>"1553734X", "doi"=>"10.1371/journal.pcbi.1003158", "scopus"=>"2-s2.0-84880773423", "pmid"=>"23874194", "sgr"=>"84880773423"}, "id"=>"e738813e-f9a2-396b-b19e-5575d55cd7a0", "abstract"=>"Lysine specific demethylase-1 (LSD1/KDM1A) in complex with its corepressor protein CoREST is a promising target for epigenetic drugs. No therapeutic that targets LSD1/CoREST, however, has been reported to date. Recently, extended molecular dynamics (MD) simulations indicated that LSD1/CoREST nanoscale clamp dynamics is regulated by substrate binding and highlighted key hinge points of this large-scale motion as well as the relevance of local residue dynamics. Prompted by the urgent need for new molecular probes and inhibitors to understand LSD1/CoREST interactions with small-molecules, peptides, protein partners, and chromatin, we undertake here a configurational ensemble approach to expand LSD1/CoREST druggability. The independent algorithms FTMap and SiteMap and our newly developed Druggable Site Visualizer (DSV) software tool were used to predict and inspect favorable binding sites. We find that the hinge points revealed by MD simulations at the SANT2/Tower interface, at the SWIRM/AOD interface, and at the AOD/Tower interface are new targets for the discovery of molecular probes to block association of LSD1/CoREST with chromatin or protein partners. A fourth region was also predicted from simulated configurational ensembles and was experimentally validated to have strong binding propensity. The observation that this prediction would be prevented when using only the X-ray structures available (including the X-ray structure bound to the same peptide) underscores the relevance of protein dynamics in protein interactions. A fifth region was highlighted corresponding to a small pocket on the AOD domain. This study sets the basis for future virtual screening campaigns targeting the five novel regions reported herein and for the design of LSD1/CoREST mutants to probe LSD1/CoREST binding with chromatin and various protein partners.", "link"=>"http://www.mendeley.com/research/expanding-druggable-space-lsd1corest-epigenetic-target-new-potential-binding-regions-druglike-molecu", "reader_count"=>38, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Researcher"=>11, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>2, "Other"=>6, "Student > Bachelor"=>3, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Researcher"=>11, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>2, "Other"=>6, "Student > Bachelor"=>3, "Professor"=>3}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>19, "Medicine and Dentistry"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>10, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>10}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>19}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Denmark"=>2, "Italy"=>2}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1122818"], "description"=>"<p>Left column: X-ray structure of LSD1/CoREST bound to the H3-histone N-terminal tail (PDB ID: 2V1D); LSD1 (orange cartoons), CoREST (cyan cartoons), H3-tail (purple spheres), and the FAD cofactor (green tubes) are highlighted. LSD1/CoREST has a well-characterized amine oxidase domain (AOD) that binds the H3-histone N-terminal tail and demethylates the fourth lysine residues of the H3-histone N-terminal tail. Connected to the AOD is the SWIRM domain crucial for substrate recognition <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003158#pcbi.1003158-Yang1\" target=\"_blank\">[26]</a>. A unique feature of LSD1 is the Tower domain that serves as interface for associating with CoREST, and is required for nucleosome binding. Middle column: MD centroids of the reduced unbound conformational ensemble. Right column: MD centroids of the reduced H3-histone N-terminal tail-bound conformational ensemble. MD centroids are color coded from red (high centroid rank) to blue (low centroid rank).</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development", "x-ray", "heterogeneous", "conformations", "conformational", "clustering", "molecular"], "article_id"=>748514, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003158.g001", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_LSD1_CoREST_X_ray_structure_and_heterogeneous_conformations_from_conformational_clustering_of_molecular_dynamics_trajectories_/748514", "title"=>"Comparison of LSD1/CoREST X-ray structure and heterogeneous conformations from conformational clustering of molecular dynamics trajectories.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-18 04:33:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1122819"], "description"=>"<p>The DSV <i>Visualize</i> function allows the user to easily view predicted binding sites on multiple receptor structures by mapping FTMap Consensus Sites (CSs) and SiteMap sites on a receptor and displaying the results with Visual Molecular Dynamics (VMD). DSV automated processing of an ensemble of structures displays the predicted binding sites onto a representative user-defined reference structure (in this case the top ranked MD centroid). After sourcing the DSV script, a single text on the command line instructs DSV to load the reference structure, align the remaining centroids to the reference, and then display FTMap CSs as spheres and SiteMap sites as surfaces. The spheres are sized according to CS rank and colored according to their centroid rank. The SiteMap surfaces are also colored according to centroid rank.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development", "visualizer", "workflow", "graphical"], "article_id"=>748515, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003158.g002", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Druggable_Site_Visualizer_DSV_workflow_and_graphical_interface_/748515", "title"=>"Druggable Site Visualizer (DSV) workflow and graphical interface.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-18 04:33:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1122820"], "description"=>"<p>FTMap CSs are shown as red spheres on X-ray structures (<b>Panel A</b>) and as spheres colored according to representative MD centroids (<b>Panel B</b>). In each panel, the top row displays the top five CSs reported by FTMap; the bottom row displays the top 10 CSs. DSV displays sphere size correlated to FTMap CS rank. For graphical purposes, the FTMap CSs from all representative MD centroids are mapped onto the structure of the highest ranked MD centroid. If present during the FTMap mapping calculations, the H3-histone N-terminal tail (present in 2V1D and MD Bound) and the SNAIL1 N-terminal peptide (present in 2Y48) are highlighted as purple spheres. The H3-histone N-terminal tail and SNAIL1 N-terminal peptide were rendered more transparent when there was overlap with FTMap spheres. Solid arrows highlight new CSs at the AOD/SWIRM interface not observed in the X-ray structures and hollow arrows highlight new CSs at the AOD/Tower interface not observed in the X-ray structures (cf. 2V1D H3-Absent with MD Bound H3-Absent and 2V1D H3-Present with MD Bound H3-Present).</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development", "visualizer", "ftmap", "sites"], "article_id"=>748516, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003158.g003", "stats"=>{"downloads"=>2, "page_views"=>94, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Druggable_Site_Visualizer_DSV_mapping_of_the_top_FTMap_consensus_sites_CSs_/748516", "title"=>"Druggable Site Visualizer (DSV) mapping of the top FTMap consensus sites (CSs).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-18 04:33:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1122821"], "description"=>"<p>The top-five FTMap consensus sites (red spheres) and SiteMap sites (surfaces) are displayed as calculated for X-ray and MD structures. DSV <i>Visualize</i> was used to display the FTMap and SiteMap results, coloring the SiteMap sites according the MD centroid rank. In all cases SiteMap surfaces overlap with FTMap spheres and predict druggable regions beyond FTMap predicted space.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development", "ftmap", "sitemap", "druggability"], "article_id"=>748517, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003158.g004", "stats"=>{"downloads"=>1, "page_views"=>33, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_between_FTMap_and_SiteMap_druggability_mapping_/748517", "title"=>"Comparison between FTMap and SiteMap druggability mapping.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-18 04:33:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1122822"], "description"=>"<p>SiteMap sites on LSD1/CoREST overlap with crystal contact regions. <b>Panel A</b> shows the crystal-packing interactions of three LSD1/CoREST molecules represented as red, blue, and grey opaque surfaces. In <b>Panels B</b> and <b>C</b> LSD1/CoREST are represented as transparent surfaces and SiteMap sites are colored surfaces to correspond with the unit in <b>Panel A</b>, e.g. the blue SiteMap sites in <b>Panel B</b> originate from the blue LSD1/CoREST in <b>Panel A</b>.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development"], "article_id"=>748518, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003158.g005", "stats"=>{"downloads"=>4, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_LSD1_CoREST_crystal_contacts_/748518", "title"=>"LSD1/CoREST crystal contacts.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-18 04:33:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1122823"], "description"=>"<p>The peptide (green) and LSD1 (brown) are highlighted (nitrogen atoms: blue; oxygen atoms: red). The unbiased 2Fo-Fc electron density map (contoured at 1.2 σ level) was calculated prior to inclusion of the peptide in the refinement. Residue Pro1 of the bound peptide was not visible in the electron density and, therefore, was not included in the model. See also <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003158#pcbi-1003158-t001\" target=\"_blank\">Table 1</a> and <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003158#pcbi-1003158-g008\" target=\"_blank\">Figure 8</a>, region D.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development", "pro-leu-ser-phe-leu-val", "binding"], "article_id"=>748519, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003158.g006", "stats"=>{"downloads"=>3, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Crystallographic_data_of_Pro_Leu_Ser_Phe_Leu_Val_binding_to_a_region_on_the_surface_of_LSD1_CoREST_AOD_/748519", "title"=>"Crystallographic data of Pro-Leu-Ser-Phe-Leu-Val binding to a region on the surface of LSD1/CoREST AOD.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-18 04:33:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1122824"], "description"=>"<p><b>Panel A</b>: SiteMap surfaces from H3-bound MD centroids are mapped onto the structure of LSD1/CoREST bound to Pro-Leu-Ser-Phe-Leu-Val peptide (purple spheres: PDB code 3ZMV). DSV <i>Visualize</i> was used to map the SiteMap sites from MD bound centroids onto 3ZMV with SiteMap surfaces colored according to centroid rank. The close-up views show SiteMap sites overlapping with the bound peptide. <b>Panel B</b>: Residues Arg312 and Phe320 are key for Pro-Leu-Ser-Phe-Leu-Val peptide binding and SiteMap predictions. Left: The X-ray conformation of Arg312 and Phe320 (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003158#pcbi-1003158-g006\" target=\"_blank\">Figure 6</a>); SiteMap failed to predict a hot spot in this region after removal of the peptide coordinates. Middle: Instead, Arg312 and Phe320 adopted conformations that opened the Pro-Leu-Ser-Phe-Leu-Val binding pocket leading to SiteMap predictions of a clear hot spot. Right: MD snapshots in which residues Arg312 and Phe320 adopted conformations that closed binding site and prevented the prediction of SiteMap hot spots in the Pro-Leu-Ser-Phe-Leu-Val binding site.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development", "reduced", "ensemble", "shows", "sitemap", "sites", "peptide", "binding", "lsd1"], "article_id"=>748520, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003158.g007", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MD_reduced_ensemble_shows_SiteMap_sites_predicted_small_peptide_binding_to_LSD1_AOD_/748520", "title"=>"MD reduced ensemble shows SiteMap sites predicted small peptide binding to LSD1 AOD.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-18 04:33:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1122825"], "description"=>"<p>The five most favorable druggable regions thus far unexplored are highlighted using colored spheres and named based on their location: SANT2/Tower interface (green, A), AOD/Tower interface (red, B), SWIRM/AOD interface (blue, C), Peptide binding region (yellow, D), and small AOD pocket (grey, E). LSD1 (orange), CoREST (cyan), and the H3-histone N-terminal tail (purple) are shown as cartoons. <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003158#pcbi-1003158-t001\" target=\"_blank\">Table 1</a> summarizes the residues in each identified druggable region. See also <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003158#pcbi.1003158.s002\" target=\"_blank\">Figure S2</a> for a description of the <i>Select-residues</i> criterion used for analysis.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development", "small-molecule", "peptide", "druggable"], "article_id"=>748521, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003158.g008", "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Potential_small_molecule_and_peptide_LSD1_CoREST_druggable_sites_/748521", "title"=>"Potential small-molecule and peptide LSD1/CoREST druggable sites.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-18 04:33:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1122826"], "description"=>"<p>LSD1/CoREST residues within each predicted druggable region.</p>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development", "residues", "druggable"], "article_id"=>748522, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003158.t001", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_LSD1_CoREST_residues_within_each_predicted_druggable_region_/748522", "title"=>"LSD1/CoREST residues within each predicted druggable region.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-07-18 04:33:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1122827", "https://ndownloader.figshare.com/files/1122828"], "description"=>"<div><p>Lysine specific demethylase-1 (LSD1/KDM1A) in complex with its corepressor protein CoREST is a promising target for epigenetic drugs. No therapeutic that targets LSD1/CoREST, however, has been reported to date. Recently, extended molecular dynamics (MD) simulations indicated that LSD1/CoREST nanoscale clamp dynamics is regulated by substrate binding and highlighted key hinge points of this large-scale motion as well as the relevance of local residue dynamics. Prompted by the urgent need for new molecular probes and inhibitors to understand LSD1/CoREST interactions with small-molecules, peptides, protein partners, and chromatin, we undertake here a configurational ensemble approach to expand LSD1/CoREST druggability. The independent algorithms FTMap and SiteMap and our newly developed Druggable Site Visualizer (DSV) software tool were used to predict and inspect favorable binding sites. We find that the hinge points revealed by MD simulations at the SANT2/Tower interface, at the SWIRM/AOD interface, and at the AOD/Tower interface are new targets for the discovery of molecular probes to block association of LSD1/CoREST with chromatin or protein partners. A fourth region was also predicted from simulated configurational ensembles and was experimentally validated to have strong binding propensity. The observation that this prediction would be prevented when using only the X-ray structures available (including the X-ray structure bound to the same peptide) underscores the relevance of protein dynamics in protein interactions. A fifth region was highlighted corresponding to a small pocket on the AOD domain. This study sets the basis for future virtual screening campaigns targeting the five novel regions reported herein and for the design of LSD1/CoREST mutants to probe LSD1/CoREST binding with chromatin and various protein partners.</p></div>", "links"=>[], "tags"=>["Biochemistry", "enzymes", "Enzyme structure", "proteins", "protein structure", "Biochemistry simulations", "Biomacromolecule-ligand interactions", "chemical biology", "drug discovery", "biophysics", "Biophysics simulations", "Protein chemistry", "Computational biology", "Biochemical simulations", "Biophysic al simulations", "genetics", "epigenetics", "Histone modification", "computational chemistry", "molecular dynamics", "Molecular mechanics", "medicinal chemistry", "organic chemistry", "Physical organic chemistry", "Computer modeling", "Computing methods", "Computer graphics", "Drugs and devices", "Drug research and development", "druggable", "epigenetic", "binding", "regions", "drug-like"], "article_id"=>748523, "categories"=>["Information And Computing Sciences", "Medicine", "Chemistry", "Biological Sciences"], "users"=>["James C. Robertson", "Nate C. Hurley", "Marcello Tortorici", "Giuseppe Ciossani", "Maria Teresa Borrello", "Nadeem A. Vellore", "A. Ganesan", "Andrea Mattevi", "Riccardo Baron"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1003158.s001", "https://dx.doi.org/10.1371/journal.pcbi.1003158.s002"], "stats"=>{"downloads"=>4, "page_views"=>36, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expanding_the_Druggable_Space_of_the_LSD1_CoREST_Epigenetic_Target_New_Potential_Binding_Regions_for_Drug_Like_Molecules_Peptides_Protein_Partners_and_Chromatin_/748523", "title"=>"Expanding the Druggable Space of the LSD1/CoREST Epigenetic Target: New Potential Binding Regions for Drug-Like Molecules, Peptides, Protein Partners, and Chromatin", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-07-18 04:33:45"}

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Relative Metric

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