Identification of Novel Smoothened Ligands Using Structure-Based Docking
Publication Date
August 04, 2016
Journal
PLOS ONE
Authors
Celine Lacroix, Inbar Fish, Hayarpi Torosyan, Pranavan Parathaman, et al
Volume
11
Issue
8
Pages
e0160365
DOI
http://doi.org/10.1371/journal.pone.0160365
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0160365
Scopus
84983354657
Mendeley
http://www.mendeley.com/research/identification-novel-smoothened-ligands-using-structurebased-docking
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Mendeley | Further Information

{"title"=>"Identification of novel smoothened ligands using structure-based docking", "type"=>"journal", "authors"=>[{"first_name"=>"Celine", "last_name"=>"Lacroix", "scopus_author_id"=>"57198033083"}, {"first_name"=>"Inbar", "last_name"=>"Fish", "scopus_author_id"=>"55799024500"}, {"first_name"=>"Hayarpi", "last_name"=>"Torosyan", "scopus_author_id"=>"56841628500"}, {"first_name"=>"Pranavan", "last_name"=>"Parathaman", "scopus_author_id"=>"57190814671"}, {"first_name"=>"John J.", "last_name"=>"Irwin", "scopus_author_id"=>"7202726820"}, {"first_name"=>"Brian K.", "last_name"=>"Shoichet", "scopus_author_id"=>"7006416338"}, {"first_name"=>"Stephane", "last_name"=>"Angers", "scopus_author_id"=>"55919937800"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"611725956", "pmid"=>"27490099", "sgr"=>"84983354657", "doi"=>"10.1371/journal.pone.0160365", "isbn"=>"1932-6203", "scopus"=>"2-s2.0-84983354657"}, "id"=>"04c555b9-76db-3604-ab8c-11a74b21a6ca", "abstract"=>"The seven transmembrane protein Smoothened is required for Hedgehog signaling during embryonic development and adult tissue homeostasis. Inappropriate activation of the Hedgehog signalling pathway leads to cancers such as basal cell carcinoma and medulloblastoma, and Smoothened inhibitors are now available clinically to treat these diseases. However, resistance to these inhibitors rapidly develops thereby limiting their efficacy. The determination of Smoothened crystal structures enables structure-based discovery of new ligands with new chemotypes that will be critical to combat resistance. In this study, we docked 3.2 million available, lead-like molecules against Smoothened, looking for those with high physical complementarity to its structure; this represents the first such campaign against the class Frizzled G-protein coupled receptor family. Twenty-one high-ranking compounds were selected for experimental testing, and four, representing three different chemotypes, were identified to antagonize Smoothened with IC50 values better than 50 μM. A screen for analogs revealed another six molecules, with IC50 values in the low micromolar range. Importantly, one of the most active of the new antagonists continued to be efficacious at the D473H mutant of Smoothened, which confers clinical resistance to the antagonist vismodegib in cancer treatment.", "link"=>"http://www.mendeley.com/research/identification-novel-smoothened-ligands-using-structurebased-docking", "reader_count"=>19, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>3, "Researcher"=>2, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>2, "Student > Master"=>6, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>3, "Researcher"=>2, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>2, "Student > Master"=>6, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>8, "Medicine and Dentistry"=>3, "Agricultural and Biological Sciences"=>3, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>3, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Chemistry"=>{"Chemistry"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>1}

Scopus | Further Information

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