SYSTEMS AND METHODS OF SELECTING COMPOUNDS WITH REDUCED RISK OF CARDIOTOXICITY USING CARDIAC SODIUM ION CHANNEL MODELS

摘要

Provided herein are systems and methods for selecting compounds that havereduced risk ofcardiotoxicity or which are not likely to be cardiotoxic. As an example, asystem and methodcan include a computational dynamic model combined with a high throughputscreening insilico that mimics an important ion channels associated with cardiotoxicity,namely thehuman human cardiac sodium ion (hNa v1.5) channel). In certain embodiments,steeredmolecular dynamics simulations are used to identify key residues of thechannel's permeationpathways that are then used in the high throughput screening. Also providedherein aresystems and methods for redesigning compounds that are predicted to becardiotoxic basedon the model and the high throughput screening.