Computational Simulations of PROTAC as a BRD4 Inhibitor in Neuroblastoma

Neuroblastoma (NB) is the most common tumor of nerve tissue and is the most common cancer in babies. The oncogene MYCN gets amplified in the disease, which can be inhibited by targeting the BRD4 protein.[1] PROTAC, a protein degradation tool, is an emerging therapeutic strategy that targets disease-causing proteins.[2] The current research work focuses on two proteins: BRD4 protein and E3 ubiquitin (E3) ligase protein. The BRD4 protein plays an important role in gene regulation and cell functioning, and its malfunction can lead to Neuroblastoma. On the other hand, the E3 protein acts as a cancer suppressor and can inhibit BRD4 protein activity. To destroy the BRD4 protein, the E3 protein should come into proximity to each other. We hypothesize that the aptamers used in this study will bind strongly at the interface between the BRD4 and E3 ligase protein. This is facilitated by a chemical compound known as PROTAC, which binds to both the BRD4 and E3 proteins, bringing them close together to form a BRD4-PROTAC-E3 complex. In the current work, we have used molecular docking to understand the BRD4-PROTAC-E3 interactions, and based on this knowledge, we have designed novel 30 PROTACs and computed their pharmaceutical properties and based on our analysis Aptamer II formed strong interactions with both the proteins. Finding novel PROTACs will aid in computer-aided designing of potent, cost-effective, and less side-effect PROTACs against cancer.