Life Sciences & Biotechnology
Title : | Unraveling the mechanism of mutant p53-p73 interactions: Useful insights for rational drug design against cancer using computational tools |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Projesh Kumar Roy, Indian Institute Of Technology Madras (IIT Madras) Chennai, Tamil Nadu |
Timeline Start Year : | 2022 |
Timeline End Year : | 2024 |
Contact info : | projesh.roy@gmail.com |
Details
Executive Summary : | The p73 transcription factors, part of the p53 protein family, are crucial for various aspects of human development and cancer prevention. However, nearly half of human cancers have a mutated p53 protein, while the p73 protein is rarely mutated. This has led to increased interest in cancer biologists. The TAp73 isoform of p73 protein can induce apoptosis independently, providing an alternative route to control cell proliferation. A major cause of low tumor suppressor activity in cancerous cells is the binding of mutant p53 to TAp73 protein, which prevents TAp73-tetramer formation and lowers its transcriptional activity. Several drug molecules have been proposed to inhibit the formation of complexes and up-regulate TAp73 protein, but their full structure and mechanisms are not yet known. This project aims to elucidate the full structural features of TAp73 protein and understand the mechanism of mutant p53-p73 complex formation. Computer simulations will be used to perform detailed atomistic molecular dynamics simulations, building several full-scale mutant p53-p73 dimer models. Understanding these protein complexes will help differentiate the functionalities of different mutant p53 proteins, and the free energy profiles of the complex formation will be essential in formulating inhibitory drug molecules targeting different mutant p53 proteins. The project will also focus on developing small molecule drugs to prevent the binding of mutant p53 and p73 protein in cancerous cells. Further fine-tuning of these drug molecules will increase selectivity and functionality, and high-performance drugs will be selected for clinical trials. |
Organizations involved