Designing tomorrow’s drugs

1. Designing tomorrow’s drugs Adrian Mulholland Centre for Computational Chemistry School of Chemistry, University of Bristol 30th January 2010

2. Why do we need new drugs? • For emerging diseases (e.g. to combat new strains of flu; to circumvent bacterial antibiotic resistance) • To avoid side-effects of current drugs • More specific drugs tailored to individual patients (e.g. based on genetic differences) • For diseases without current effective treatments

3. Drug discovery and development is a slow process • Currently it takes approximately 15 years to go from an idea to a marketable drug • Investment of £100s millions needed for each drug • New drug approvals are decreasing alarmingly

4. A crisis in drug discovery • Fewer new drugs are being approved 1 B. Hughes, Nature Reviews Drug Discovery 8, 93-96 (February 2009).

5. We need new, better ways to design and develop new drugs • Computer-aided design and molecular modelling can help • New methods based on quantum mechanics • More accurate

6. What are drugs? • E.g. ibuprofen – an ‘over-the-counter’ painkiller

8. Ibuprofen – a common painkiller • Like most drugs, ibuprofen is a small molecule

9. How does ibuprofen work? • Like most drugs, ibuprofen is a small molecule, and binds to a large protein molecule in the body • The protein is an enzyme – a biological catalyst; its job is to make molecules by a chemical reaction • Ibuprofen stops the enzyme working • It is an enzyme inhibitor

10. A biochemical pain signal • This enzyme adds oxygen to make a hormone molecule O2

11. How does ibuprofen work? Ibuprofen inhibits (blocks) this enzyme, stopping the pain signal from being made Transmits pain signals to the brain, causes inflammation

12. Enzymes are biological catalysts • Almost all chemical reactions in a cell are catalysed by enzymes • All aspects of biochemistry depend on enzyme catalysis • Catalysts make reactions happen faster but are not changed by the reaction

14. Enzymes make reactions faster by lowering the energy barrier They can do this by stabilizing the transition state, i.e. binding to it strongly

15. Enzymes as drug targets • Many drugs work by inhibiting enzymes • But how do they work – at the molecular level? • What interactions are involved? • Knowing how enzymes catalyse reactions can help in the design of new drugs

16. The active site • A small part in the enzyme where the chemical reaction happens

17. Enzyme inhibitors as drugs

18. New drugs from understanding how enzymes work • Enzymes bind transition states tightly • Design molecules that resemble the transition state • Should bind strongly to enzyme active site

19. Transition state analogues as drugs Active site Transition state Transition state analogue drug Enzyme

20. To design a drug, we need to know: • The structure of the protein (e.g. enzyme) target • Knowing the structure of the transition state for the reaction in the enzyme, and how it interacts with the enzyme, should also help a lot

21. How can we find out what proteins look like? • Can determine protein structure by X-ray crystallography • To do this, you need a crystal of the protein… • …and X-rays!

22. Protein crystals Dr. Toshiya Senda, Dept. of BioEngineering,Nagaoka University of Technology, Japan http://bio.nagaokaut.ac.jp/~senda/welcome.html

23. ‘Diamond’ synchrotron, Harwell

24. X-rays from synchrotrons

26. Protein structure from X-ray diffraction

27. Different ways of representing protein structure

28. Many drugs are enzyme inhibitors • The drug binds at the active site and stops the enzyme from working

29. Ibuprofen Ibuprofen bound to its enzyme target

30. Why do we need computer modelling? • Can do things that experiments can’t: • Model how chemical bonds break and form, i.e. model reactions in enzymes • Model transition state structures • Model how proteins move and flex • Modelling can study proteins ‘in action’ • Predict how tightly new drugs will bind

31. University of Bristol supercomputer: ‘BlueCrystal’ • Among the top 100 most powerful in the world

32. Modelling antibiotic breakdown in a bacterial enzyme

33. Modelling antibiotic breakdown in a bacterial enzyme

34. Modelling antibiotic breakdown • Understand molecular mechanisms of antibiotic resistance • Identify which groups in the enzyme are responsible for catalysing the reaction • Model the transition state • Design modified antibiotics to overcome bacterial resistance

35. The bliss molecule • Anandamide (ananda is Sanskrit for bliss) • Released naturally in the body in response to pain • An ‘endocannabinoid’

36. Natural pain relief • Stopping the breakdown of anandamide relieves pain • Anandamide is broken down by fatty acid amide hydrolase • Inhibitors of fatty acid amide hydrolase are potentially useful drugs • Clinically useful aspects of marijuana without side-effects

37. Fatty acid amide hydrolase • The enzyme that breaks down the bliss molecule • Modelling shows how anandamide is broken down • Shows how inhibitors bind to the enzyme • Helping in the design of new, better medicines

38. Modelling shows how the drug binds to the enzyme • Model of URB597 as it reacts and binds to the enzyme

39. Natural pain relief • URB597: an inhibitor with pain relief properties, ready to enter clinical trials

40. Tamiflu (Oseltamivir)

41. Tamiflu

42. Influenza neuraminidase • Flu enzyme, drug target • Large, complex, difficult to model

43. Tamiflu molecule binds at enzyme active site It binds because it is a transition state analogue

44. Neuraminidase inhibitors as flu drugs

45. Calculate which molecule binds more tightly to the protein • i.e. which is the better potential drug?

46. Modelling drug metabolism

47. Modelling drug metabolism • Drugs are broken down by enzymes • Aim to predict how drugs interact with each other, or other substances, in the body • E.g. grapefruit juice contains enzyme inhibitors that slow drug breakdown!

48. Modelling drug metabolism Use molecular modelling of reactions of drugs in enzymes to help to predict: • Toxicity • Side effects • Genetic effects (in future: tailor drug and dose to the patient) • Adverse drug reactions

49. Modelling ibuprofen metabolism

50. Computer-aided drug design produces drugs that save lives • Nelfinavir: HIV protease inhibitor