PHAY0020 THE PROCESS OF DRUG DISCOVERY 2023Processing

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Java Python PHAY0020

THE PROCESS OF DRUG DISCOVERY (TPODD 1)

MAY 2023

1. Answer BOTH parts of the question.

The use of computational based tools for successful drug discovery relies on the use of a complete high-quality structural model of the target molecule, typically downloaded from the protein data bank (PDB).

a) Discuss the processes you would use to ensure the initial coordinate model of an enzyme from the PDB, containing a ligand in the protein active site, is made suitable to run computational based docking experiments. Highlight the challenges and the methods available to help validate your starting model. (50% of marks)

b) Given the aim to design a novel inhibitor to modulate the enzyme’s function: describe the computational approaches you might undertake to characterise and understand the target receptor binding pocket and its molecular properties, and ONE structure-based experimental approach you would utilise to generate a viable hit compound. (50% of marks)

2. Answer ALL parts of the question.

PT-1 was recently identified from high-throughput screening campaign to be active against the RNA methyltransferase NSUN2. To identify more potent NSUN2 inhibitors, a small library of compounds (PT-2 to PT-16) was synthesised using PT-1 as the lead compound, and their inhibitory activities are presented in the table below. Answer the following questions based on the chemical structures and data provided.

a) Which drug/lead discovery strategy was used in the above approach? Provide a brief description of this method. (25% of marks)

b) Based on the observed IC50 values of compounds PT-1 to PT-7, what information can be deduced about the active site of NSUN2? (20% of marks)

c) Based on the observed IC50 values of compounds PT1 and PT-8 to PT-13, what information can be deduced about the active site of NSUN2? (30% of marks)

d) The most potent NSUN2 inhibitor identified is PT-13 (IC50 = 0.21 µM). Suggest an analogue of PT-13 which is likely to be more potent. Provide the chemical structure of this analogue. (25% of marks)

3. Answer ALL parts of the question.

You are working in a team developing drugs to treat central nervous system condit PHAY0020 THE PROCESS OF DRUG DISCOVERY 2023Processing ions. You have a hit compound which is currently undergoing development. The structure of the hit compound and some of its properties are given below.

a) You suspect that the hit compound is a substrate of an ATP-dependent efflux pump in the blood-brain barrier. Describe THREE different approaches you could use to determine whether this is the case. Provide examples of tools/techniques you would employ in each approach. (20% of marks)

b) Discuss whether the hit compound is likely to be passively permeable across the blood-brain barrier. Your discussion should include the provided properties (cLogP and PSA) and any other relevant properties which can be derived from the chemical structure. (50% of marks)

c) Chemical approaches can be used to improve the permeability of compounds across the blood-brain barrier. For the hit compound above:

i. Describe ONE chemical approach which could be used to improve the hit compound’s blood-brain barrier permeability. (10% of marks)

ii. Suggest ONE way in which the structure of the hit compound might be modified in the approach you suggested in part i. Explain why this modification is likely to improve blood-brain barrier permeability. (Note that no details of how to conduct the required chemical transformation are needed). (10% of marks)

iii. What are the potential drawback(s) which might be encountered when employing the approach you suggested in part i? (10% of marks)

4. Answer BOTH parts of the question.

Large-scale mapping of the proteome identified 11 cardiovascular proteins with causal evidence of involvement in human disease that can potentially act as drug targets. As a scientist in a small bioinformatics company with excellent resources, you are tasked with identifying one protein that can be validated as a drug target.

a) Describe the use of bioinformatics tools to select only one protein for target validation by a contract research organization (CRO). To support your answer, suggest which resources could be utilized and discuss the properties that a protein should possess to be a good drug target. (70% of marks)

b) Suggest ONE genomic method that a CRO can conduct to validate the potential of the selected protein as a drug target. Briefly describe this method and justify the selection of your chosen method