Targeted Inhibition of Oncogenic p300 Proteins Using Novel PROTACs for Hepatocellular Carcinoma Therapy

The p300 protein helps control gene expression and other essential cell processes in the human body. When p300 doesn’t work the way, it's supposed to, it can lead to hepatocellular carcinoma (HCC). PROTACs are innovative chemical compounds designed to degrade target proteins by recruiting them to E3 ligases for ubiquitination. Recently, a novel PROTAC targeting p300 protein has been discovered targeting hepatocellular carcinoma, one of the most common solid tumors. we hypothesize that chemical modifications in PROTACs can enhance their potency, developing more effective structures for therapeutic applications. To test this hypothesis, molecular docking simulations were employed to identify PROTACs capable of binding to both p300 and E3 ligase with high affinity. First, the p300 and E3 Ligase proteins were obtained from AlphaFold 3, a deep learning-based method. Next, molecular docking simulations revealed the p300-E3 ligase complex structure. In the next step, chemical alteration in the PROTAC 3D structure was performed to design the PROTAC library. Finally, the PROTACs interactions with p300-E3 ligase protein were computed to get the p300-PROTAC-E3 Ligase complex. These simulations provided insights into the interactions between PROTACs and the protein complexes, guiding the design of improved compounds. The docking results were further validated using a deep learning-based method, P2Rank. Based on our knowledge, this is the first computational modeling study on PROTAC-mediated p300 protein degradation. The current research will aid in developing personalized cancer treatments, utilizing PROTACs to target specific oncogenic proteins like p300, thus offering a promising strategy for precision medicine.