<i>In Silico</i> Modeling of PROTAC-Mediated Ternary Complexes: Validation and Application

Abstract

In this work, four methods are described and validated for generating in silico ensembles of PROTAC-mediated ternary complexes. Filters based on characteristics of the proposed ternary complexes are developed to identify those that resemble known crystal structures. We then show how to use these modeling techniques a priori to discriminate the PROTAC-mediated degradation behavior of a mutant protein vs its wild type, of three closely related targets, and among three different PROTAC molecules.