Advances in designing ternary complexes: Integrating in-silico and biochemical methods for PROTAC optimisation in target protein degradation.

Target protein degradation (TPD) is an emerging approach to mitigate disease-causing proteins. TPD contains several strategies, and one of the strategies that gained immersive importance in recent times is Proteolysis Targeting Chimeras (PROTACs); the PROTACs recruit small molecules to induce the poly-ubiquitination of disease-causing protein by hijacking the ubiquitin-proteasome system (UPS) by bringing the E3 ligase and protein of interest (POI) into appropriate proximity. The steps involved in designing and evaluating the PROTACs remain critical in optimising the PROTACs to degrade the POI. It is observed that using in-silico and biochemical methods to study the ternary complexes (TCs) of the POI-PROTAC-E3 ligase is essential to understanding the structural activity, cooperativity, and stability of formed TCs. A better understanding of the above-mentioned leads to an appropriate rationale for designing the PROTACs targeting the disease-causing proteins. In this review, we tried to summarise the approaches used to design the ternary complexes, i.e., in-silico and in-vitro methods, to understand the behaviour of the PROTAC-induced ternary complexes.