{"id":14720,"date":"2024-06-27T07:15:22","date_gmt":"2024-06-27T07:15:22","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=14720"},"modified":"2024-06-27T07:17:01","modified_gmt":"2024-06-27T07:17:01","slug":"2024-experimentally-validated-modeling-of-dynamic-drug-herg-channel-interactions-reproducing-the-binding-mechanisms-and-its-importance-in-action-potential-duration","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2024-experimentally-validated-modeling-of-dynamic-drug-herg-channel-interactions-reproducing-the-binding-mechanisms-and-its-importance-in-action-potential-duration\/","title":{"rendered":"2024 &#8211; Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration."},"content":{"rendered":"<div id=\"abss0002\">\n<p id=\"cesectitle0003\" class=\"u-h4 u-margin-m-top u-margin-xs-bottom\">Background and Objective<\/p>\n<p id=\"spara011\">Assessment of drug cardiotoxicity is critical in the development of new compounds and modeling of drug-binding dynamics to hERG can improve early cardiotoxicity assessment. We previously developed a methodology to generate Markovian models reproducing preferential state-dependent binding properties, trapping dynamics and the onset of I<sub>Kr<\/sub>\u00a0block using simple voltage clamp protocols. Here, we test this methodology with real I<sub>Kr<\/sub>\u00a0blockers and investigate the impact of drug dynamics on action potential prolongation.<\/p>\n<\/div>\n<div id=\"abss0003\">\n<p id=\"cesectitle0004\" class=\"u-h4 u-margin-m-top u-margin-xs-bottom\">Methods<\/p>\n<p id=\"spara012\">Experiments were performed on HEK cells stably transfected with hERG and using the Nanion SyncroPatch 384i. Three protocols, P-80, P0 and P 40, were applied to obtain the experimental data from the drugs and the Markovian models were generated using our pipeline. The corresponding static models were also generated and a modified version of the O\u00b4Hara-Rudy action potential model was used to simulate the action potential duration.<\/p>\n<\/div>\n<div id=\"abss0004\">\n<p id=\"cesectitle0005\" class=\"u-h4 u-margin-m-top u-margin-xs-bottom\">Results<\/p>\n<p id=\"spara013\">The experimental Hill plots and the onset of I<sub>Kr<\/sub>\u00a0block of ten compounds were obtained using our voltage clamp protocols and the models generated successfully mimicked these experimental data, unlike the CiPA dynamic models. Marked differences in APD prolongation were observed when drug effects were simulated using the dynamic models and the static models.<\/p>\n<\/div>\n<div id=\"abss0005\">\n<p id=\"cesectitle0006\" class=\"u-h4 u-margin-m-top u-margin-xs-bottom\">Conclusions<\/p>\n<p id=\"spara014\">These new dynamic models of ten well-known I<sub>Kr<\/sub>\u00a0blockers constitute a validation of our methodology to model dynamic drug\u2013hERG channel interactions and highlight the importance of state-dependent binding, trapping dynamics and the time-course of I<sub>Kr<\/sub>\u00a0block to assess drug effects even at the steady-state.<\/p>\n<\/div>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,77],"therapeutic_areas":[143],"target_categories":[61],"target_families":[333],"targets":[92],"resource_keyword":[],"class_list":["post-14720","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","application_areas-cell-ipscs-profiling","therapeutic_areas-assay-development-and-validation","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv11-1-herg"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/14720","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=14720"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=14720"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=14720"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=14720"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=14720"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=14720"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=14720"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=14720"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=14720"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}