{"id":13307,"date":"2023-03-28T14:08:20","date_gmt":"2023-03-28T14:08:20","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13307"},"modified":"2024-01-10T14:11:37","modified_gmt":"2024-01-10T14:11:37","slug":"2023-cryo-em-reveals-an-unprecedented-binding-site-for-nav1-7-inhibitors-enabling-rational-design-of-potent-hybrid-inhibitors","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2023-cryo-em-reveals-an-unprecedented-binding-site-for-nav1-7-inhibitors-enabling-rational-design-of-potent-hybrid-inhibitors\/","title":{"rendered":"2023 &#8211; Cryo-EM reveals an unprecedented binding site for NaV1.7 inhibitors enabling rational design of potent hybrid inhibitors"},"content":{"rendered":"<p>The voltage-gated sodium (Na<sub>V<\/sub>) channel Na<sub>V<\/sub>1.7 has been identified as a potential novel analgesic target due to its involvement in human pain syndromes. However, clinically available Na<sub>V<\/sub>\u00a0channel-blocking drugs are not selective among the nine Na<sub>V<\/sub>\u00a0channel subtypes, Na<sub>V<\/sub>1.1\u2013Na<sub>V<\/sub>1.9. Moreover, the two currently known classes of Na<sub>V<\/sub>1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. To this point understanding of the structure\u2013activity relationships of the acylsulfonamide class of Na<sub>V<\/sub>1.7 inhibitors, exemplified by the clinical development candidate\u00a0GDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor bound to voltage-sensing domain 4 (VSD4). To advance inhibitor design targeting the Na<sub>V<\/sub>1.7 channel, we pursued high-resolution ligand-bound Na<sub>V<\/sub>1.7-VSD4 structures using cryogenic electron microscopy (cryo-EM). Here, we report that\u00a0GDC-0310\u00a0engages the Na<sub>V<\/sub>1.7-VSD4 through an unexpected binding mode orthogonal to the arylsulfonamide inhibitor class binding pose, which identifies a previously unknown ligand binding site in Na<sub>V<\/sub>\u00a0channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl- and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, our study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design. This work also underscores an important role of the membrane bilayer in the optimization of selective Na<sub>V<\/sub>\u00a0channel modulators targeting VSD4.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50],"therapeutic_areas":[55],"target_categories":[61],"target_families":[332],"targets":[116],"resource_keyword":[],"class_list":["post-13307","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","therapeutic_areas-cns","target_categories-voltage-gated-ion-channels","target_families-nav-channels","targets-nav1-7"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/13307","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=13307"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=13307"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=13307"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=13307"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=13307"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=13307"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=13307"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=13307"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=13307"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}