Smarter drug design
An advanced experimental technique linked to high powered computation is becoming an increasingly important tool for MWC researchers developing new drugs.
Discovery and development of new drugs involves many years of research and testing, and there is global interest in alternative methods capable of accelerating the path from identifying a target molecule to a drug in the clinic. MWC scientists throughout NZ are collaborating to improve a novel drug discovery technique – called “transition state analysis” – and open up new pipelines of effective medicines.
Enzymes are protein molecules that carry out chemical reactions in the body and in infectious agents. They are common targets for drugs because stopping an enzyme from working can switch off disease processes involving that particular enzyme. Most drugs are designed to fit tightly into a part of the enzyme called the active site and stop it from working. Transition state analysis involves a lot of very detailed analysis of the target enzyme. MWC Principal Investigator Emily Parker from Victoria University’s Ferrier Research Institute explains: “Some drug design techniques treat the active site as just a static shape that you need to slot the drug molecule into. However, the shape of an enzyme is not fixed, it changes all the time, as the atoms and bonds vibrate and move – this movement is part of their normal process. Understanding how they work and move allows us to design drugs that can fit into the enzyme very specifically and very tightly and stop the enzyme in its tracks.”
The use of this detailed information for drug design was established by Professor Vern Schramm at Albert Einstein College of Medicine in New York. Ferrier Institute Professors Peter Tyler, Gary Evans and Richard Furneaux, have been working with Professor Schramm for over 20 years using transition state analysis information to make drugs that block enzymes. This collaboration designed and synthesised the cancer drug Mundesine, which was approved in Japan during 2017 for the treatment of patients with peripheral T-cell lymphoma, the first approval for an agent of this type in the world.
Now with support from the MWC and the Ferrier Research Institute, Emily and Gary along with Professor Vic Arcus from the University of Waikato, have established the transition state analysis capability wholly in NZ. The MWC team, and in particular Dr Scott Cameron, are carrying out transition state analysis on enzyme targets critical to antimicrobial resistance as part of an MWC Flagship programme. MWC research fellow Dr Gert-Jan Moggré in Emily’s research group has analysed the transition state of adenosine triphosphate phosphoribosyl-transferase, an enzyme that is essential for bacterial survival and a target for drug development. This work was recently published in the journal ACS Chemical Biology*.While the initial enzymes they are focussed on are in the antimicrobial resistance space, Emily and Gary say that transition state analysis can also be applied to enzymes that are important in cancer and diabetes. In the future, transition state analysis may well change the shape of drug design in the Maurice Wilkins Centre.
For more information, see Moggre, G. J., M. B. Poulin, P. C. Tyler, V. L. Schramm and E. J. Parker, Transition State Analysis of Adenosine Triphosphate Phosphoribosyltransferase. ACS Chemical Biology (2017) 12(10): 2662-2670.
A three-dimensional representation of a transition state analogue bound within the active site of a target protein
Image courtesy of Dr Scott Cameron