Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors
Publication Date
May 15, 2017
Authors
Ornella Di Pietro, Jordi Juárez Jiménez, Diego Muñoz Torrero, Charles A. Laughton, et al
Volume
12
Issue
5
Pages
e0177683
DOI
https://dx.plos.org/10.1371/journal.pone.0177683
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0177683
Scopus
85019456908
Mendeley
http://www.mendeley.com/research/unveiling-novel-transient-druggable-pocket-bace1-through-molecular-simulations-conformational-analys
Events
Loading … Spinner

Mendeley | Further Information

{"title"=>"Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors", "type"=>"journal", "authors"=>[{"first_name"=>"Ornella", "last_name"=>"Di Pietro", "scopus_author_id"=>"55744830100"}, {"first_name"=>"Jordi", "last_name"=>"Juarez-Jimenez", "scopus_author_id"=>"54079713600"}, {"first_name"=>"Diego", "last_name"=>"Muñoz-Torrero", "scopus_author_id"=>"6604023002"}, {"first_name"=>"Charles A.", "last_name"=>"Laughton", "scopus_author_id"=>"7005668861"}, {"first_name"=>"F.", "last_name"=>"Javier Luque", "scopus_author_id"=>"6506273625"}], "year"=>2017, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"616160596", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0177683", "isbn"=>"1111111111", "scopus"=>"2-s2.0-85019456908", "sgr"=>"85019456908"}, "id"=>"d9d219a7-c00b-3a55-bdfc-af6a8cd84048", "abstract"=>"The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer's disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challeng-ing. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC 50 80 nM) designed by synergistic combination of two fragments—huprine and rhein— that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8–14, 154–169 and 307–318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable \" floppy \" pocket would enable the bind-ing of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligo-methylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications intro-duced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors.", "link"=>"http://www.mendeley.com/research/unveiling-novel-transient-druggable-pocket-bace1-through-molecular-simulations-conformational-analys", "reader_count"=>9, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>4, "Student > Master"=>1, "Lecturer > Senior Lecturer"=>1, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>4, "Student > Master"=>1, "Lecturer > Senior Lecturer"=>1, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>2}, "reader_count_by_subdiscipline"=>{"Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>0}

Scopus | Further Information

{"@_fa"=>"true", "link"=>[{"@_fa"=>"true", "@ref"=>"self", "@href"=>"https://api.elsevier.com/content/abstract/scopus_id/85019456908"}, {"@_fa"=>"true", "@ref"=>"author-affiliation", "@href"=>"https://api.elsevier.com/content/abstract/scopus_id/85019456908?field=author,affiliation"}, {"@_fa"=>"true", "@ref"=>"scopus", "@href"=>"https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85019456908&origin=inward"}, {"@_fa"=>"true", "@ref"=>"scopus-citedby", "@href"=>"https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85019456908&origin=inward"}], "prism:url"=>"https://api.elsevier.com/content/abstract/scopus_id/85019456908", "dc:identifier"=>"SCOPUS_ID:85019456908", "eid"=>"2-s2.0-85019456908", "dc:title"=>"Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors", "dc:creator"=>"Di Pietro O.", "prism:publicationName"=>"PLoS ONE", "prism:eIssn"=>"19326203", "prism:volume"=>"12", "prism:issueIdentifier"=>"5", "prism:pageRange"=>nil, "prism:coverDate"=>"2017-05-01", "prism:coverDisplayDate"=>"May 2017", "prism:doi"=>"10.1371/journal.pone.0177683", "citedby-count"=>"9", "affiliation"=>[{"@_fa"=>"true", "affilname"=>"Universitat de Barcelona", "affiliation-city"=>"Barcelona", "affiliation-country"=>"Spain"}], "pubmed-id"=>"28505196", "prism:aggregationType"=>"Journal", "subtype"=>"ar", "subtypeDescription"=>"Article", "article-number"=>"e0177683", "source-id"=>"10600153309", "openaccess"=>"1", "openaccessFlag"=>true}

Counter

  • {"month"=>"5", "year"=>"2017", "pdf_views"=>"63", "xml_views"=>"13", "html_views"=>"597"}
  • {"month"=>"6", "year"=>"2017", "pdf_views"=>"34", "xml_views"=>"1", "html_views"=>"104"}
  • {"month"=>"7", "year"=>"2017", "pdf_views"=>"40", "xml_views"=>"4", "html_views"=>"57"}
  • {"month"=>"8", "year"=>"2017", "pdf_views"=>"29", "xml_views"=>"1", "html_views"=>"45"}
  • {"month"=>"9", "year"=>"2017", "pdf_views"=>"21", "xml_views"=>"1", "html_views"=>"57"}
  • {"month"=>"10", "year"=>"2017", "pdf_views"=>"15", "xml_views"=>"1", "html_views"=>"83"}
  • {"month"=>"11", "year"=>"2017", "pdf_views"=>"10", "xml_views"=>"0", "html_views"=>"156"}
  • {"month"=>"12", "year"=>"2017", "pdf_views"=>"25", "xml_views"=>"1", "html_views"=>"277"}
  • {"month"=>"1", "year"=>"2018", "pdf_views"=>"49", "xml_views"=>"1", "html_views"=>"71"}
  • {"month"=>"2", "year"=>"2018", "pdf_views"=>"14", "xml_views"=>"0", "html_views"=>"34"}
  • {"month"=>"3", "year"=>"2018", "pdf_views"=>"20", "xml_views"=>"3", "html_views"=>"20"}
  • {"month"=>"4", "year"=>"2018", "pdf_views"=>"28", "xml_views"=>"0", "html_views"=>"26"}
  • {"month"=>"5", "year"=>"2018", "pdf_views"=>"10", "xml_views"=>"3", "html_views"=>"12"}
  • {"month"=>"6", "year"=>"2018", "pdf_views"=>"11", "xml_views"=>"3", "html_views"=>"18"}
  • {"month"=>"7", "year"=>"2018", "pdf_views"=>"8", "xml_views"=>"3", "html_views"=>"33"}
  • {"month"=>"8", "year"=>"2018", "pdf_views"=>"1", "xml_views"=>"1", "html_views"=>"8"}
  • {"month"=>"9", "year"=>"2018", "pdf_views"=>"9", "xml_views"=>"0", "html_views"=>"26"}
  • {"month"=>"10", "year"=>"2018", "pdf_views"=>"7", "xml_views"=>"1", "html_views"=>"23"}
  • {"month"=>"11", "year"=>"2018", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"21"}
  • {"month"=>"12", "year"=>"2018", "pdf_views"=>"10", "xml_views"=>"0", "html_views"=>"19"}
  • {"month"=>"1", "year"=>"2019", "pdf_views"=>"20", "xml_views"=>"0", "html_views"=>"18"}
  • {"month"=>"2", "year"=>"2019", "pdf_views"=>"14", "xml_views"=>"0", "html_views"=>"17"}
  • {"month"=>"3", "year"=>"2019", "pdf_views"=>"19", "xml_views"=>"0", "html_views"=>"24"}
  • {"month"=>"4", "year"=>"2019", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"16"}
  • {"month"=>"5", "year"=>"2019", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"21"}
  • {"month"=>"6", "year"=>"2019", "pdf_views"=>"6", "xml_views"=>"0", "html_views"=>"15"}
  • {"month"=>"7", "year"=>"2019", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"16"}
  • {"month"=>"8", "year"=>"2019", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"12"}
  • {"month"=>"9", "year"=>"2019", "pdf_views"=>"17", "xml_views"=>"0", "html_views"=>"11"}
  • {"month"=>"10", "year"=>"2019", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"17"}
  • {"month"=>"11", "year"=>"2019", "pdf_views"=>"6", "xml_views"=>"1", "html_views"=>"18"}
  • {"month"=>"12", "year"=>"2019", "pdf_views"=>"10", "xml_views"=>"0", "html_views"=>"18"}
  • {"month"=>"1", "year"=>"2020", "pdf_views"=>"8", "xml_views"=>"1", "html_views"=>"6"}
  • {"month"=>"2", "year"=>"2020", "pdf_views"=>"15", "xml_views"=>"1", "html_views"=>"13"}
  • {"month"=>"3", "year"=>"2020", "pdf_views"=>"17", "xml_views"=>"1", "html_views"=>"18"}
  • {"month"=>"4", "year"=>"2020", "pdf_views"=>"23", "xml_views"=>"0", "html_views"=>"12"}
  • {"month"=>"5", "year"=>"2020", "pdf_views"=>"25", "xml_views"=>"1", "html_views"=>"11"}
  • {"month"=>"6", "year"=>"2020", "pdf_views"=>"18", "xml_views"=>"1", "html_views"=>"7"}
  • {"month"=>"7", "year"=>"2020", "pdf_views"=>"13", "xml_views"=>"0", "html_views"=>"12"}
  • {"month"=>"8", "year"=>"2020", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"11"}
  • {"month"=>"9", "year"=>"2020", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"11"}
  • {"month"=>"10", "year"=>"2020", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"15"}
  • {"month"=>"11", "year"=>"2020", "pdf_views"=>"3", "xml_views"=>"0", "html_views"=>"7"}

PMC Usage Stats

  • {"unique-ip"=>"1", "full-text"=>"0", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"5"}
  • {"unique-ip"=>"13", "full-text"=>"11", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"6"}
  • {"unique-ip"=>"11", "full-text"=>"9", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"7"}
  • {"unique-ip"=>"13", "full-text"=>"11", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"8"}
  • {"unique-ip"=>"19", "full-text"=>"18", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
  • {"unique-ip"=>"15", "full-text"=>"14", "pdf"=>"11", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
  • {"unique-ip"=>"10", "full-text"=>"12", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"12"}
  • {"unique-ip"=>"5", "full-text"=>"7", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"1"}
  • {"unique-ip"=>"1", "full-text"=>"1", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"2"}
  • {"unique-ip"=>"11", "full-text"=>"9", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"3"}
  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"1"}
  • {"unique-ip"=>"12", "full-text"=>"15", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"7", "full-text"=>"8", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"3", "full-text"=>"2", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"4"}
  • {"unique-ip"=>"14", "full-text"=>"14", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
  • {"unique-ip"=>"12", "full-text"=>"9", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"6", "full-text"=>"5", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"13", "full-text"=>"16", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"1", "full-text"=>"1", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"8", "full-text"=>"7", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"7", "full-text"=>"6", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"10", "full-text"=>"7", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"11", "full-text"=>"9", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"7", "full-text"=>"6", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"10", "full-text"=>"9", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"6", "full-text"=>"2", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"21", "full-text"=>"13", "pdf"=>"17", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"6", "full-text"=>"9", "pdf"=>"23", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"9", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"7", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"7", "full-text"=>"3", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"4", "full-text"=>"5", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"7", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"9", "full-text"=>"12", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"8", "full-text"=>"4", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}

F1000Prime | Further Information

Loading … Spinner
There are currently no alerts