{"id":6102,"date":"2023-02-17T06:56:13","date_gmt":"2023-02-17T06:56:13","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2014-multi-generational-pharmacophore-modeling-for-ligands-to-the-cholane-steroid-recognition-site-in-the-%ce%b21-modulatory-subunit-of-the-bkca-channel\/"},"modified":"2023-02-17T06:56:14","modified_gmt":"2023-02-17T06:56:14","slug":"2014-multi-generational-pharmacophore-modeling-for-ligands-to-the-cholane-steroid-recognition-site-in-the-%ce%b21-modulatory-subunit-of-the-bkca-channel","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2014-multi-generational-pharmacophore-modeling-for-ligands-to-the-cholane-steroid-recognition-site-in-the-%ce%b21-modulatory-subunit-of-the-bkca-channel\/","title":{"rendered":"2014 &#8211; Multi-Generational Pharmacophore Modeling for Ligands to the Cholane Steroid-Recognition Site in the \u03b21 Modulatory Subunit of the BK(Ca) Channel"},"content":{"rendered":"<p>Large conductance, voltage- and Ca<sup>2+<\/sup>-gated K<sup>+<\/sup>\u00a0(BKCa) channels play a critical role in smooth muscle contractility and thus represent an emerging therapeutic target for drug development to treat vascular disease, gastrointestinal, bladder and uterine disorders. Several compounds are known to target the ubiquitously expressed BKCa\u00a0channel-forming \u03b1 subunit. In contrast, just a few are known to target the BKCa\u00a0modulatory \u03b21\u00a0subunit, which is highly expressed in smooth muscle and scarce in most other tissues. Lack of available high-resolution structural data makes structure-based pharmacophore modeling of \u03b21\u00a0subunit-dependent BKCa\u00a0channel activators a major challenge. Following recent discoveries of novel BKCa\u00a0channel activators that act via \u03b21\u00a0subunit recognition, we performed ligand-based pharmacophore modeling that led to the successful creation and fine-tuning of a pharmacophore over several generations. Initial models were developed using physiologically active cholane steroids (bile acids) as template. However, as more compounds that act on BKCa\u00a0\u03b21\u00a0have been discovered, our model has been refined to improve accuracy. Database searching with our best-performing model has uncovered several novel compounds as candidate BKCa\u00a0\u03b21\u00a0subunit ligands. Eight of the identified compounds were experimentally screened and two proved to be activators of recombinant BKCa\u00a0\u03b21\u00a0complexes. One of these activators, sobetirome, differs substantially in structure from any previously reported activator.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[44],"resource_type":[75],"application_areas":[50],"therapeutic_areas":[],"target_categories":[61,335],"target_families":[354],"targets":[216],"resource_keyword":[],"class_list":["post-6102","resource_library","type-resource_library","status-publish","hentry","products_tags-patchliner","resource_type-publication","application_areas-ion-channels","target_categories-voltage-gated-ion-channels","target_categories-intracellular-regulated-ion-channels","target_families-calcium-and-sodium-activated-potassium-channels-kca-and-kna","targets-kca1-1"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/6102","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=6102"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=6102"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=6102"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=6102"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=6102"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=6102"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=6102"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=6102"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=6102"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}