In order to process your request, CCG requires the following information from you. CCG does not sell, rent, or trade personally identifiable information with third parties. Please see CCG's Privacy Notice for more information on why we need this information and how it will be used.
Modeling Ternary Complexes with Molecular Glues: Making Sense of a Sticky Situation
Targeted protein degradation has emerged in recent years as a new modality to control protein levels in vivo. Among the many competing degradation technologies, most research to date has focused on heterobifunctional protein degraders (such as PROTACs), although inherent concerns about the molecular properties of these “large small molecules” has sparked intense interest in the development of smaller degraders, such as molecular glues. As a rule, molecular glues are smaller and are thus more attractive as potential therapeutics – but because a single molecule is responsible for simultaneously binding to two disparate proteins, the rational discovery of molecular glues to date has proven difficult. In this work, we will discuss multiple computational techniques implemented in MOE for modeling ternary complexes containing molecular glues. Special focus will be paid to lessons learned from our well-established PROTAC modeling toolset. In particular, it will be shown that the most effective molecular glue models result from treating molecular glues as “linkerless PROTACs.” Finally, recent work in developing techniques to prioritize prospective molecular glue designs based on their predicted degradation efficacy will be presented.