The AAA ATPase p97 is an essential protein involved in numerous cellular processes and plays a key role in multiple aspects of protein homeostasis. Its functional diversity is mediated through the interaction with a large number of distinct cofactors. Due to its significant role in regulating a variety of physiological responses, p97 has emerged as a potential therapeutic target. In this project we will use a combined approach using computer-based methods including virtual screening of molecular databases and biochemical/biophysical techniques as well as X-ray crystallography to develop cofactor-specific inhibitors. These inhibitors will be important to dissect the molecular and cellular functions of p97, thus helping to unravel their specific role in controlling p97 activity and may be potential alternatives to existing anti-cancer drug candidate molecules.