Structure-Based Discovery of a Cryptic Druggable Pocket in TP53 C238Y: Implications for Targeted Therapy

SIMPLE SUMMARY TP53 gene is really important for keeping our cells healthy. It does this by fixing damaged DNA, managing cell growth, and telling cells to die if they're too damaged to repair. But when TP53 has mutations,these defenses stop working, and cells start growing out of control. One of the big problems in trying to create drugs that target TP53 is that it's very flexible and doesn't have obvious places where drugs can easily attach. This has led to it being called "undruggable”. However, some recent findings suggest that certain mutations can change the protein's shape, revealing hidden areas where drugs might be able to bind. In this research, I used computer-based methods to study the C238Y mutation in TP53 and see how it changes the protein's structure. The results showed that this mutation causes some reshaping of the protein's surface, exposing a previously hidden pocket that could be a target for drugs. These results suggest that we should take another look at TP53 as a potential target for cancer drugs, which could lead to the development of drugs that work specifically against certain TP53 mutations . Abstract Mutations in the TP53 gene are frequently found in many different types of human cancers These mutations interfere with important functions that normally prevent tumors, like controlling cell growth and causing programmed cell death. When TP53 can't do its job, cells start multiplying without control, and the cell's genetic material becomes unstable. Even though TP53 has long been known to be a key player in cancer it's been very difficult to develop drugs that target it. This is largely because of its flexible structure and the lack of clear binding sites for drugs. But, recent studies indicate that specific mutations can cause structural changes in TP53, creating new potential binding sites that could be useful for drug development. In this study, I used computer modeling and structural biological analysis to examine the c238y tp53 mutation . The results showed that this mutation dramatically reshapes the protein in the vicinity — it exposes a hidden pocket that could be a promising target for drugs. These results pave the way to conceptualising and designing therapies that are mutationally specific with the end goal being to disrupt or restore the default function of malfunctioning TP53 in cancer. This structural study lays the foundation for a follow-up phase involving virtual screening and drug-binding validation targeting the revealed cryptic pocket. These steps can help translate this structural finding into fruitful therapeutic strategies. The findings reinforce a growing realization in the field: that druggability in proteins like TP53, often labelled as too disordered or flexible to target, may in fact be highly dependent on the specific mutations they carry. This flexibility may offer a unique opportunity for designing mutation-specific treatments—bringing us closer to personalized cancer therapies. his manuscript presents a detailed computational and structural analysis of the C238Y mutant, revealing a cryptic and druggable pocket specific to this mutation. and the study provides the foundation for docking