Define the terms C, n, ?, and ? in the Hansch equation. Comment on the reliability and accuracy of the Hansch equation. What sort of properties (in terms of ? and ?) should the R group possess in order to maximise biological activity?

(i) Define the terms C, n, ?, and ? in the Hansch equation. Comment on the reliability and accuracy of the Hansch equation. What sort of properties (in terms of ? and ?) should the R group possess in order to maximise biological activity? Which property is the most important?

(ii) Explain why Hansch analysis is particularly accurate when the R group is in positions `meta` or `,para` to the NH, but less reliable when it is in the `ortho` position.

(iii) Discuss, in outline, the use of Craig Plots in optimising biological activity.

(iv) One concern about structures like (2) is its potential interaction with the hERG receptor. What is the hERG receptor and why is this interaction a problem? What is the pharmacophore model for general hERG interaction? Does (2) conform to this pharmacophore?

(v) Given that the pKa of a derivative of (2) is 5.5, is it more likely to be absorbed from the stomach (pH = 1.2) or intestine (pH = 6.4)?

(b) Molecular docking is widely used in hit identification and lead optimisation for drug development. Define, with examples, the concept of molecular docking.

Problem 3 - Answer ALL parts of this question.

(a) Explain what is meant by the terms pharmacogenomics and pharmacometabonomics.

(b) Describe how pharmacogenomics and pharmacometabonomics can help deliver personalised medicine. In particular, describe with examples the following:

(i) How genetic differences between people can affect the interaction between a drug and the patient.

(ii) How environmental factors may affect a patient`s response to a drug.

Problem 4 - Answer ALL parts of this question.

(a) Answer BOTH parts

(i) Describe 2 different strategies for targeting the Epidermal Growth Factor signalling pathway in cancer. Include named examples of drugs developed from these strategies in your answer.

(ii) Briefly explain why screening for RAS mutations is recommended before prescribing Erbitux.