title: Novel targets in drug design: enzymes in the protein ubiquitylation pathway.
abstract: Protein ubiquitylation is a pathway by which many proteins are selectively degraded. Its role has been shown in processes such as cell division and differentiation, oncogenesis, apoptosis, DNA repair, membrane transport and the removal of abnormal proteins. The ubiquitylation pathway enzymes are an insufficiently researched area for drug development. A genetic method has been developed (supported by computational biology) to identify potentially useful small molecules that will have a positive impact on our battle against cancer and other diseases. In silico screening is used for initial selection of drug-like compounds. This method is based on docking three-dimensional chemical libraries onto the target enzyme's functional site for initial screens using a computational scheme, followed by genetic and in vivo methods for hit optimisation. Focus has been on using the ubiquitin conjugation pathway as target for therapeutic intervention against cancer and potent inhibitors of ubiquitylation subpathways have been obtained (including those that are vital for the survival of aggressive cancer cells/tumours). Leads from the development of in vitro inhibitors provided a direction for the development of in vivo inhibitors as investigational tools, and as promising therapeutic agents.
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences and Karmanos Cancer Institute, 259 Mack Avenue, Room 3142, Detroit, Michigan 48201, USA. abanerj@genetics.wayne.edu.
authors.forename: Amit
authors.initials: A
authors.lastname: Banerjee