Cytochrome P450 17A1 selectivity – important for anti-cancer therapy
The aim of the project is to develop selective inhibitors for cytochrome P450 (CYP) 17A1 for use in anti-cancer therapy.
Initially, the enzymatic mechanism will be mapped by computational methods. Subsequently and utilizing the knowledge about the mechanism, selective inhibitors will be identified, respectively designed. Finally, potentially interesting ligands will be tested and characterized.
Background and contents
When a foreign compound, like a drug, enters the human organism, a number of defence systems are activated. One of them is the ubiquitous multifunctional cytochrome P450 (CYP) family of enzymes that metabolizes about 80 % of drugs, by transforming structurally diverse compounds to water-soluble derivatives by oxidation. The seven most prevalent isoforms of cytochrome P450 enzymes are responsible for almost all metabolism of all known drugs.
It has been known for long time that certain CYPs may convert foreign compounds, xenobiotics, to reactive metabolites, and that some of these metabolites may be carcinogenic. New findings – that several endogenous metabolizing CYPs are directly related to various cancer types – have turned the CYPs into direct targets for anti-cancer therapy.
In this PhD project, we will focus on the CYP17A1 for three reasons: 1) CYP17A1 is a proven target for treatment of prostate cancer and perhaps also for treatment of breast cancer, 2) the 3D structure of the CYP17A1 complexed with abiraterone and a related compound recently have been determined and published in Nature by Emily Scott, who will be part of the project, and 3) developing selective nonsteroidal inhibitors for CYP17A1 represents a special challenge.
CYP17A1 is unique enzyme, because the same enzyme catalyses two subsequent processes: 1) conversion of pregnenolone to 17-a-hydroxypregnenolone (the 17-a-hydroxylase process) and 2) conversion of the 17-a-hydroxypregnenolone to dehydroepiandrosterone (the C17,20-lyase process). Only a limited number of inhibitors of CYP17A1 have been reported in the literature, and nearly all of these are steroidal inhibitors, which also may interact with the androgen receptor. We have in several cases documented that we by computational methods are able to identify new ligands for various drug targets, i.e. b-lactamases, human peptide transporter, the 5-HT2A receptor, and most recently CYP1A2. Based on our experience with modelling enzymatic reactions, especially CYP-mediated reactions and virtual screening, we are confident that it will be possible to identify selective inhibitors for CYP17A1 within the framework of a PhD project.
The project is expected to lead to an improved understanding of the structural requirements for ligand binding to and inhibition of CYP 17A1, i.e. to a establish structure/mechanism-activity relationships. The PhD project is also expected to identify/yield selective compounds, which may provide the basis for further work towards therapeutically interesting compounds.
Professor Flemming Steen Jørgensen and associate professor Lars Olsen, Biostructural Research, Department of Drug Design and Pharmacology, University of Copenhagen.
The project is a collaborative project between the Biostructural Research group at University of Copenhagen and associate professor Emily E. Scott at University of Kansas. The project will combine the computational expertise on the CYPs present in the BR group and the experimental expertise present in Scott’s group. The PhD student is expected to spend a considerable time in Scott’s laboratory.
An applicant with experience in computational chemistry (in particular molecular dynamics simulations, docking and virtual screening), thermodynamic studies or protein-ligand studies will be preferred. Experimental experience with handling proteins will also be an advantage.
Deadline for applications is Thursday 8. November 2012 at 12:00.
See http://www.farma.ku.dk/index.php/Jobs/3744/0/ for the official announcement and