Arthritis and Diabetes Flashcards
How can we improve the action of metal complexes?
Improvements can be made by using dual agents - e.g. vanadium and allixin can be complexed to allow vanadium to mimic insulin and allixin to counteract some side effects of diabetes.
What types of behaviour can discount a drug for use in the human body?
Hydrolysis and deactivation of the drug in short periods of time
How can we try to be as representative as possible in studies of drugs before clinical trials and animal testing?
Consider a range of conditions the drug may experience in the body and design experiments to simulate these conditions and see what happens.
Can you give a brief overview of HSAB theory?
Hard acids and hard bases like to bind (small non polarisable) and soft acids and soft bases like to bind (diffuse orbitals, polarisable).
How does vanadium work as a drug for diabetes?
Vanadium complexes work by mimicing insulin and binding at receptors. PTM involving phosphorylation to allow sugar to enter cell. Vanadate addition is irreversible, so sugar continues to enter the cell (blood sugar level drops?)
How do metals travel through the body?
Metals bind to moving proteins in the blood, e.g. HSA, transferrin
What factors should we be considering when making new drugs?
Important to consider what species may be formed in the body (e.g. vanadium hydrolysis products in the stomach vs through the body)
What can make finding mechanistic detail about metals in medicine difficult?
Drugs can bind to many different places and it’s difficult to tell which interaction is responsible for what. Also made harder when therapeutic benefit is only seen over a longer period of time!
What activity does auranofin (drug for arthritis) show?
Travels through blood stream bound to HSA (proton NMR evidence + X-ray), binds to Kathepsin K enzyme preventing breakdown of collagen, binds to other proteins switching off TrxR and glutathione reductase, and substitutes for zinc in zinc fingers to modify structure and inhibit protein function.
