E-Resources Use and Assessment

The coursework associated with this module is designed to enable you to find, and assess the quality of, information associated with a particular drug. Knowing where to find key information and assess its quality and relevance is vital when undertaking independent research, such as the research you will undertake as part of your final year project.
The first piece of coursework for this module requires you to use a range of electronic resources to find information about your drug. You then need to consider the quality and usefulness of the information. Note that each student will be allocated a unique drug to investigate.
There are two workshop sessions associated with this first piece of coursework. The first workshop involves finding and assessing the quality of literature resources, web pages and formal documents concerning your drug. The second workshop will introduce you to freely accessible chemistry resources that are available on the internet and elsewhere. These resources can be used to obtain (or predict) key information concerning drugs of interest or may be used to optimise the design of new drugs. Four key aspects of a drug’s properties will be investigated:
– Basic information on the drug (chemical identifiers, use and structure)
– Information on physico-chemical properties
– Information on Absorption, Distribution, Metabolism and Elimination (ADME) properties
– Information on Toxicity

Use this proforma to record the results of your research. Please type this form, you may copy and paste information as appropriate; use Arial font size 11. This proforma should be submitted as per instructions provided during the workshop; feedback will be provided within 15 working days of the deadline for submission. This piece of coursework contributes 30% to your mark for this module.

Staff are available during the workshop to help and advise on using the e-resources, however you should attempt to answer questions labelled Q1 – Q3 independently.

Workhop – Part 1: Literature
(i) Finding, Citing and Assessing the Quality of Journal Articles Relating to Your Drug
Using (for example) “Web of Science” find FOUR journal articles that relate to your drug.
•   Using the table below give the correct citation for each article in the style stated in the Guidelines for Authors for the Journal of Pharmacy and Pharmacology.
•   Cite papers from FOUR different journals.
•   Assess the quality of each journal, e.g. in terms of its Impact Factor, possible scientific reputation etc.

Journal Article 1. Citation (According to Journal of Pharmacy and Pharmacology Guidelines)

Assessment of the Quality of the Journal:

Journal Article 2. Citation (According to Journal of Pharmacy and Pharmacology Guidelines)

Assessment of the Quality of the Journal:

Journal Article 3. Citation (According to Journal of Pharmacy and Pharmacology Guidelines)

Assessment of the Quality of the Journal:

Journal Article 4. Citation (According to Journal of Pharmacy and Pharmacology Guidelines)

Assessment of the Quality of the Journal:

[8 marks]

(ii) Finding Further Details Relating to Topics Identified in a Relevant Journal Article
Whilst the information contained within a journal article may be very useful on its own, another use for journal articles is using them to direct your search for additional information. For example a journal article may give results of a particular experimental method but may not provide the details of the method itself. However, the article should provide a reference for the method used and you may therefore use the references listed within the article to find more details about a particular aspect of the research. In the next section you should use the reference list from a journal article to find more detailed information about particular aspects of the work.
For ONE of the journal articles that you have cited above and have assessed as being of “high quality”, select THREE references from the list of references that are given at the end of the article. For each of these three references give the author(s) and the year of the publication. If there are more than three authors, list the first three then write “et al”. Identify which areas of the research these three references will provide more information on and why the additional information may be beneficial (50 words maximum for each).
Author(s) Year Topic covered in research article / benefit of information
Relates to journal article [ ] above

[6 marks]

(iii) Finding Internet Sites Relating to Your Drug
Using an internet search engine e.g. Google, find FOUR internet sites that relate to your drug.
•   Using the table below give the URL of the web-sites; use FOUR different web-sites with different information and reliability of content; Give the date accessed for each web-site
•   Briefly describe the content of each website (20 words maximum for each)
•   Assess the reliability of the information on each web-site. Place the websites in the table below in the order of the most reliable (and unbiased) first to the least reliable last. Justify the position of the websites in the table.
•   Web-sites must be publicly available, social networking sites (e.g. Facebook etc) should only be given if they do NOT require login / registration etc.

URL for Website 1 (MOST RELIABLE AND UNBIASED) Date Website 1 Accessed

09/03/2015
http://www.nhs.uk/Conditions/Osteoporosis/Pages/MedicineOverview.aspx?condition=Osteoporosis&medicine=Alendronate%20sodium&preparationAlendronic%20acid%2010mg%20tablets

Brief Description of the Content of Website 1 (20 Words Maximum)
This website provides information about the uses

Assessment of the Reliability of the Information in Website 1
This website is reliable …………….

URL for Website 2 Date Website 2 Accessed

Brief Description of the Content of Website 2 (20 Words Maximum)

Assessment of the Reliability of the Information in Website 2

URL for Website 3 Date Website 3 Accessed

Brief Description of the Content of Website 3 (20 Words Maximum)

Assessment of the Reliability of the Information in Website 3

URL for Website 4 Date Website 4 Accessed
http://en.wikipedia.org/wiki/Alendronic_acid

Brief Description of the Content of Website 4 (20 Words Maximum)

Assessment of the Reliability of the Information in Website 4

[8 marks]

(iv) Finding An Official Document Relating to Your Drug
Using an internet search engine e.g. Google, find an official document relating to your drug.

•   Using the table below give the details of the document and the web-site it is found on (please use Arial 11pt)
•   Examples could include a piece of legislation (e.g. UK or EU), a patent, clinical guidance or governance etc.
•   Briefly state the purpose of the document (20 words maximum).

URL for the Document Date Document Accessed

https://www.nice.org.uk/guidance/ta161/resources/guidance-alendronate-etidronate-risedronate-raloxifene-strontium-ranelate-and-teriparatide-for-thesecondary-prevention-of-osteoporotic-fragility-fractures-in-postmenopausal-women-amended-pdf

Details of the Document e.g. Authors (if Applicable), Title etc.

Brief Description of the Document /

Purpose of the Document

[3 marks]

Workshop – Part 2: Chemoinformatics
(i) Finding Basic Information Regarding Your Drug
Use a chemistry information resource (such as ChemSpider, Drugbank etc) to find the following information.

Molecular weight   249.096 Da
CAS number   66376-36-1
Systematic (IUPAC) name   (4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid
SMILES   NCCCC(O)(P(O)(O)=O)P(O)(O)=O
Melting point (or boiling point or vapour pressure)   234 °C
Summarise (in approximately 50 words) the use(s) of your drug; its therapeutic class / other drugs in the same therapeutic class and potential side effect(s) of the drug
For the treatment and prevention of osteoporosis in women and Paget’s disease of bone in both men and women.Alendronate, a second-generation bisphosphonate is the first member of a group of drugs which strengthens bone. Alendronate is used to reduce hypercalcemia in tumor-induced bone disease, to treat corticosteroid-induced osteoporosis and Paget’s disease, and to prevent osteoporosis in postmenopausal women.The action of Alendronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Alendronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.
[5 marks]

(ii) Drug structure

Use the Accelrys Draw package (available on the university network) to obtain a pictorial representation of your drug and copy this into the box below. Follow instructions in the guidance document.

[5 marks]

(iii) Finding / Predicting Key Properties for Drugs

– Use the KOWWIN package (follow instructions in guidance document) to obtain a predicted value for the logarithm of the octanol:water partition coefficient (log P) for your drug. If it is available, record the measured / experimental log P for the drug.

– Use the WSKOW package (follow instructions in guidance document) to obtain a predicted logarithm of the aqueous solubility (log S) for your drug. If it is available record the measured / experimental log S.

Briefly state which amendments you could make to your drug’s structure to (a) increase its aqueous solubility and (b) decrease its aqueous solubility. You can try amending the SMILES string for your drug as appropriate and checking to see if the modifications have successfully increased or decreased the aqueous solubility.

Record all your of results in the table below.

Predicted log P   -0.50
Measured / Experimental log P (if available)   N/A
Predicted log S   0.415
Measured / Experimental log S (if available)   N/A
Amendment to increase log S: 1.265
C(CC(O)(P(=O)(O)O)P(=O)(O)O)C(N)O
Naser

Amendment to decrease log S:-0.368

naser

CN(C)CCCC(O)(P(=O)(O)O)P(=O)(O)O

[5 marks]

(iv) Information on ADME Properties

Absorption
Simple molecular properties can be used to screen for the likelihood of a drug being well absorbed or poorly absorbed after oral administration. Total polar surface area (TPSA), violations for Lipinski’s “Rule of Fives” and number of rotatable bonds may be used in screening.

Use the molinspiration website (follow instructions in guidance document) to determine the TPSA for your compound, whether or not there are Lipinski rule violations and the number of rotatable bonds.
Record the answers in the table below.

Total Polar Surface Area (TPSA)
161.305
Number of violations of the Lipinski Rule of “Fives” (nviolations) 1
Number of Rotatable Bonds (nrotb) 5

[5 marks]

Metabolism

Using metaprint 2d react indicate how many potential sites of metabolism are identified for your drug for each of the “normalised occurrence ratios (NORs)”, note these are colour coded:
Colour Code for NOR   Number of occurrences (i.e. number of circles of that colour highlighted for your drug)
Red   1
Orange   0
Green   4
White   4
Grey   5
[5 marks]
Click on the areas highlighted to obtain possible metabolic reactions that may occur at the sites highlighted. List THREE potential reactions that your drug may undergo.
[3 marks]
1-   Phosphorylation
2-   Alkylation
3-   Acylation

(Note if you click on the name of the reaction then you can view the potential metabolite.)

(v) Information on Toxicity
Predicting potential toxicity of drug candidates or other molecules of interest is also important within developmental research. The freely available oCHEM software is a useful tool for preliminary screening. Use this software (follow instructions in guidance document) to predict potential toxicity for your drug.

Predicting enzyme inhibition

A drug that inhibits the activity of key metabolising enzymes can potentially cause significant problems. For example enzyme inhibition may lead to higher than expected levels of a parent drug persisting in the body if the drug is co-administered with an enzyme inhibitor. oCHEM can predict whether a compound is likely to be an inhibitor of key enzymes. Following the instructions in the guidance, record whether your compound is predicted to be an inhibitor or non-inhibitor of the following enzymes:

Enzyme   Inhibitor or non-inhibitor
CYP3A4   Noninhibitor
CYP2D6   Noninhibitor
CYP2C19   Noninhibitor
CYP2C9   Noninhibitor
CYP1A2   Noninhibitor
[3 marks]

Structural Alerts for Potential Toxicity

Following the instructions in the guidance document, screen your drug against all alerts available within the oCHEM software.

Which of the alerts in oCHEM are more relevant to human health effects?
[2 marks]

Skin sensitization
Potential electrophilic agents
Reactive, unstable, toxic

How many alerts in total are identified for your drug molecule?
[2 marks]

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