Designing a chemical ’toolbox’ for the efficient inhibition of metalloenzymes

Introduction
Metalloenzymes contain metal ions with their active sites and constitute one third of all currently known enzymes. Not only do they have a prominent biological role, but many are also important targets for therapeutic intervention in a variety of disease areas. This project will use a combination of structure-based molecular design, organic synthesis, and biological evaluation to identify new types of potent and selective inhibitors of these enzymes. Not only will these molecules represent potential new drug leads, but they will also provide important information as to the requirements for potent and selective inhibition of such systems.

Project
Metalloenzymes play a crucial role in a wide variety of important biological processes and include many that are targets for therapeutic intervention. These enzymes are characterized by the fact that they contain a metal ion- typically zinc, but they can also contain other metals including iron, magnesium, and calcium, within the active site of the enzyme. Crucially, these metal ions play an important role in the catalytic mechanism of the enzyme, and the binding of small molecule inhibitors directly to/very close to, the site of the metal ion is a proven treatment strategy in a number of therapeutic areas, including cancer and cardiovascular disease.

Although a number of chemical functionalities have been used within such molecules in order to provide contact to the metal ion as a key component of the inhibition process, (for example carboxylic and hydroxamic acids, 2-hydroxypyridones, hydrazides, and thiols), use of these systems can be challenging due to the fact that as very powerful coordinators of metal atoms, non-selective inhibition to metals in other proteins, as well as inherent metabolic instability can, in some cases, result in toxicity and generally poor pharmacological properties. There is therefore a need to develop new types of functionalities to enable efficient inhibition of metalloenzymes.

For this project, the student will apply a computational modelling approach to crystal structures of important metalloenzymes in order to produce a range of inhibitors designed to have good affinity but to also show high levels of selectivity for the desired enzyme target. We will base our initial studies on a series of zinc-based metalloenzymes derived from pathogenic bacteria (which include NDM-1, VIM-2, FusB, and MCR-1), for which there are high resolution crystal structures available as well as existing biological assays (both enzymic as well as using bacteria). We would then wish to extend the work to other, less well studied metalloenzymes of high therapeutic importance such as the JAMM deubiquitinating enzymes, which play important roles in cancer. In the project, the student will adopt a design strategy which, using available crystal structures, involves creating putative inhibitors based around both well established, and more recently discovered Zn ion coordinating groups.

Recent work in this latter area at Leeds has already resulted in the structural characterization of potent and selective boronate-based inhibitors of metallo beta lactamases. This project is in collaboration with the Pharma company Domainex, who will bring vital drug discovery expertise into the project, including addressing important ‘drug likeness’ aspects of the inhibitors such as minimizing toxicity, ensuring metabolic stability, etc.

Domainex will also provide experience and training in project management in an industrial setting.

The project will provide the student with experience in;

(a) The application of computer-aided molecular design in drug discovery
(b) Advanced organic and medicinal chemical techniques.
(c) Biological assays to establish activity of enzyme inhibitors
(d) Medicinal chemistry in an industrial environment.

The student will join a vibrant and highly motivated research team at the University of Leeds, and will have access to state-of-the-art equipment and facilities for chemical biology and medicinal chemistry.

Informal enquiries can be made directly to Prof. Fishwick via email; [Email Address Removed]