In recent years, proteolysis-targeting chimeras (PROTACs) have become increasingly important in the never-ending search for new drug therapies. PROTACs are bifunctional molecules designed to harness the body’s ubiqiutin-proteosome system. PROTACs bind simultaneously to both their protein target and an E3 ligase, causing the target to be ubiquitinated and then subsequently degraded by the proteasome. This process of targeted protein degradation creates a number of challenges for PROTAC design. Not only must the PROTAC bind simultaneously to the ligase and the protein target, but it should allow the formation of a stable ternary complex. In addition, the PROTAC must be able to cross cell membranes to reach its protein target. As such, there is a pressing need for computational tools to assist in the design and optimisation of PROTACS.

Molecular computer simulations are widely used in the pharmaceutical industry to predict drug binding affinities and structure. PROTACS are typically larger than many small molecule drugs, and this creates distinctive challenges. In this project, we will work closely with AstraZeneca to apply molecular modelling approaches to PROTAC design and optimisation. Using experimental data provided by AstraZeneca, we will apply molecular simulation and cheminformatics to understand and rationalise PROTAC structure-function relationships, thereby generating the insights needed to optimise PROTAC design. We will focus on exploring the roles of PROTAC conformation, membrane permeability, and the structure and stability of the PROTAC-ligase-target ternary complex, on their efficacy.