代写PHAY0020 THE PROCESS OF DRUG DISCOVERY调试Haskell程序

PHAY0020

THE PROCESS OF DRUG DISCOVERY (TPODD 1)

1.       Answer BOTH parts of the question

Virtual screening against 5-hydroxytryptamine receptor (5-HT2C) resulted in a set of  ten small molecules as potential agonists.

a)        Discuss the key factors involved in the design and evaluation of CNS drugs and  propose a strategy for selection of two  compounds for further  in  vivo experiments.                                                                                (60% of marks)

b)        Propose the use of two commonly used methods for in vivo evaluation of their CNS penetration and provide the justification for this choice.   (40% of marks)

2.       Answer BOTH parts of the question

You are aiming to develop small molecule compounds to target a newly identified binding pocket adjacent to an activation loop of a protein kinase and have available both the human apoprotein and homologous ligand bound structures determined by x-ray crystallography to better than 2.5 Å resolution. Significant differences are observed between the apoprotein and homologous structures with some additional disorder in the target binding pocket.

a)       Describe how you might utilise these structures along with molecular modelling techniques and with the use of molecular mechanics to understand the observed differences between the two structures and how this can  be used to build a representative binding pocket. Also discuss how you might explore structural aspects of the binding pocket  as a starting point for structure-based drug design. Include in your answer the limitations of the methods used.                                     (60% of marks)

b)       Your collaborators provide you with coordinates for the target   kinase identifying a small molecule fragment in the binding pocket better than 1.5 Å resolution. Explain how you might grow this fragment using computational based approaches to improve the design and binding affinity to generate small molecule lead compounds.                           (40% of marks)

3.       Answer ALL parts of the question

A scientist in a biotech company believeshe has discovered a novel cell surface receptor with an important stimulatory role in cell division that might make it a good drug target in the treatment of renal cancer. His discovery was made in a kidney cell culture.

a)       When trying to convince his project manager, what sort of properties must he demonstrate that the protein receptor possesses to be a good drug target?    (25% of marks)

b)       The scientist would like the company geneticist to carry out a Genome Wide Association Study (GWAS). Explain to his project manager what this would involve and what it might show.                   (25% of marks)

c)        The scientist proposes to use his kidney cell culture to validate his receptor as a potential drug target. Explain with molecular detail TWO possible methods that the scientist might use. Highlight any difficulties and how they might be overcome.                                         (50% of marks)

4.        Answer BOTH parts of the question:

A small pharmaceutical company has decided to initiate a drug discovery project against Type 2 Diabetes Mellitus.

The Board of Directors are split between whether to pursue lead compounds from natural products or chemically synthesized sources.

a)       Write a report for the Board of Directors outlining the advantages and

disadvantages and the difficulties and solutions for drug discovery from natural products. Use examples where possible to illustrate your arguments.     (40% of marks)

b)        Explain to the Board of Directors how large libraries of chemical compounds can be synthesized and then interrogated for lead compounds. Highlight the advantages and disadvantages of these techniques.   (60% of marks)