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Frontiers in Cryo-Electron Microscopy | EK19


EK19-EPOSTER-BORRELLI-KENNETH - An expedited genes-to-drug approach using cryo-EM enabled structure based drug design


Feb 3, 2021 12:00am ‐ Feb 3, 2021 12:00am

Description

An expedited genes-to-drug approach using cryo-EM enabled structure based drug design Structure-Based Drug Design (SBDD) imparts cost-efficiency, timeliness and superior properties to target-based small molecule drug discovery. As a result, it is a preferred means of drug discovery whenever structural enablement is feasible. Advances in protein production, cryo-electron microscopy (cryo-EM) and computational chemistry are now available to extend the benefits of SBDD to more high-value drug targets. Here, we present the approach taken by Thermo Fisher Scientific and Schrödinger for joint development of new therapeutics with an example program. GeneArt® Gene-to-Proteins was used to create highly pure native protein with a concentration of 5mg/ml. The Thermo Scientific iSPA Workflow was used to solve protein ligand complex structures to a resolution of 2.6Å. Finally the Schrödinger Drug Discovery Platform used these structures to to create a validated structure-based model of the binding affinity of congeneric ligands capable of correctly separating strong binders ( < 100nM), intermediate binders ( 100nM-1uM) and weak binders ( < 1uM) with 73% accuracy from a set of 62 previously patented ligands. Author List Kenneth Borrelli, Schrodinger - kenneth.borrelli@schrodinger.com Leah Frye, Schrodinger - leah.frye@schrodinger.com Shulu Feng, Schrodinger - shulu.feng@schrodinger.com Mazdak Radjainia, ThermoFisher Scientific, mazdak.radjainia@thermofisher.com Micheal Liss, ThermoFisher Scientific, Michael.Liss@thermofisher.com Ieva Drulyte, ThermoFisher Scientific, ieva.drulyte@thermofisher.com

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