Bifunctional robots inducing targeted protein degradation.

The gaining importance of Targeted Protein Degradation (TPD) and PROTACs (PROteolysis-TArgeting Chimeras) have drawn the scientific community's attention. PROTACs are considered bifunctional robots owing to their avidity for the protein of interest (POI) and E3-ligase, which induce the ubiquitination of POI. These molecules are based on event-driven pharmacology and are applicable in different conditions such as oncology, antiviral, neurodegenerative disease, acne etc., offering tremendous scope to researchers. In this review, primarily, we attempted to compile the recent works available in the literature on PROTACs for various targeted proteins. We summarized the design and development strategies with a focus on molecular information of protein residues and linker design. Rationalization of the ternary complex formation using Artificial Intelligence including machine & deep learning models and traditionally followed computational tools are also included in this study. Moreover, details describing the optimization of PROTACs chemistry and pharmacokinetic properties are added. Advanced PROTAC designs and targeting complex proteins, is summed up to cover the wide spectrum. [Display omitted] • This review summarises the design and development aspects of PROTACs that require an extensive understanding of cooperativity and receptivity of ternary complex. • The rational PROTAC design using Artificial Intelligence methodologies such as machine & deep learning models and with the use of modernistic computational tools is elaborated. • Optimization of PROTACs chemistry, accommodation of physicochemical parameters and advanced PROTAC designs are highlighted. [ABSTRACT FROM AUTHOR]