Computational development of E3 ubiquitin ligase binding moieties in PROTACs

• Main Author: Lam, Hilbert Yuen In
• Other Authors: Mu Yuguang
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Medicine, Health and Life Sciences; PROTAC; Computer-aided drug discovery; Protein degradation
• Online Access: https://hdl.handle.net/10356/180987
• Institution: Nanyang Technological University

Proteolysis targeting chimaeras (PROTACs) are rapidly emerging small molecule drugs that exploit the cellular ubiquitin-proteasome pathway to degrade specific proteins of interest (POIs). Notably, PROTAC molecules consist of two separate moieties conjoined with a linker - one moiety binds to the POI, whereas the other binds to an E3 ubiquitin ligase which facilitates ubiquitination and marks the POI for degradation by cellular machinery. Given that these moieties can be mixed-and-matched to target specific diseased proteins with similarly distinct E3 ligases, some of which are specific to certain organs and disease phenotypes - PROTACs can be designed with organ or disease-specificity in mind, reducing the likelihood of off-target toxicity and possible side effects, all whilst maintaining high potency. Hence, there is great interest in designing novel E3 ligase-binding moieties in the field of drug discovery and pharmacology. This work consequently proposes a new computational-aided drug design (CADD) pipeline using benzene probing and virtual screening and, using this approach, identified 58 fragments that can be potentially used as E3 ligase-binding moieties in future PROTACs.