Talk:Transition state analog

Reviewer Comment #1

1. Wording of sentence in the introduction starting with “Interactions between an enzyme…” is worded in a strange way. Try and be clearer on what you are saying. Even just saying, “Enzymes interact with a substrate by means of strain or distortions, moving the substrate towards the transition state.” Or something like that.

2. I would remove medicinal chemistry or drug discovery in the sentence starting with “Research in designing transition…”, or say it differently. Maybe say, “There has been much research in designing transition state analogs for drug discovery.” It seems to me that you do not need both mentioned in this sentence.

3. Any way to move the first figure down farther too where you are talking about Renin. I think it would be fine having the figure below the paragraph as well without text wrapping.

4. I think moving the second diagram over to the right hand side of the page would be helpful.

5. Can you find a reference talking about the “Lock and Key Model” or even a paper by Hermann Fischer talking about it for a reference? That might be hard to do but a textbook reference might work well here.

6. I believe that the Michaelis complex is also called an enzyme-substrate complex and in my experience that has been the more common term so it would be good to add that in as well.

7. The sentence beginning with, “Products are then released…” doesn’t seem to fit. It would sound better if you had a transition into this sentence such as, “After formation of the enzyme-substrate complex the product is released and the enzyme is again free to bind another substrate.”

8. The first sentence in the transition state structure I would say backwards to the reactants or forward to the products. (A picture of an energy diagram could be helpful)

9. The sentence starting with, “Amino acids in an enzyme have…” mentions that the amino acids search for the transition state. Implying that they are searching for the transition state is saying that they are trying to get to that state and they will not be trying to get to a state of high energy, the enzyme and statistical mechanics is causing it to get to that state.

10. For the sentence starting with, “This slower time scale” I would again not say the enzyme is trying to find the correct alignment, it is taking longer because it needs to be oriented in the correct direction.

11. The last sentence in the first paragraph of Transition state structure again mentions finding and searching, I think you can use better words to describe this.

12. The next paragraph again used searching, the enzyme is in that set configuration due to probabilities not because it is trying to find that one state.

13. I think the last sentence of transition state structure could be worded better, “…amino acids, give enzymes their catalytic properties with high turnover numbers.“

14. The first sentence for KIE, you should mention that you compare the rates of the isotopically labeled reactant against the more common natural substrate.

15. First sentence of Determination of transition state architecture, “…structure of the enzyme of interest.” Could be worded better. Change one of the ofs.

16. First sentence in second paragraph, “…elucidate the mechanism of action of enzymes.” Could be worded better. Change one of the ofs.

17. Are there any words or ideas that can be hyperlinked to other Wikipedia articles in this section?

18. Second sentence in second paragraph has some grammatical errors say, “…which is fundamental to organic reactions. The molecular dynamic simulations provide…”

19. Sentence starting with, “The complementary method would be…” would be best if it was reworded. Say, “The complementary method would combine molecular mechanics and quantum mechanics simulation methods. Also, what is the complementary method? Can you state why it is important to only treat the catalytic regions with quantum mechanics and the rest with molecular mechanics?

20. Third diagram seem too large, having that smaller would be beneficial.

21. Singular plural mismatch when talking about methylthioadenosine nucleosidase. “…nucleosidase are enzymes that catalyze the hydrolytic…”

22. “Given the difference in distance between the N9 atom of…” Also, explain to us where the N9 atom is.

23. Early and late dissociation stage, again explain that to us.

24. “Based on the finding of different transition state structures, Schramm and coworkers…”

25. Again explain what these binding affinity values mean to us and what was significant about them. What did it tell us?

26. For thermolysin inhibitor section the first sentence, “Thermolysin is an enzyme that catalyzes the hydrolysis of peptide amide bonds. The mechanism begins with…” You should be much clearer on the mechanism taking everyone through it one step at a time. Right now there are some grammatical errors and it is not very clear. A figure of the tetrahedral transition state would help.

27. For arginase inhibitor, “Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of…” The next few sentences are also unclear. Try going through the mechanism step by step and a diagram of the tetrahedral intermediate would be helpful.

28. Don’t mention the sulphonamide group unless you show a diagram of it.

Organic Chemist 19 (talk)

Reviewer Comment #2

Introduction: The first two sentences provide a concise intro to the material. You should explain the theory behind your statement in sentence 3. The reference you chose for sentence 3 is not great (does not contain the phrase transition state at all) and the “Transition States, Analogues, and Drug Development” reference would provide a better resource to people wanting more information. Phrasing in sentence 4 is kind of awkward, consider rewording this. The last two sentences are not really appropriate for an introduction paragraph. Consider listing a couple specific transition state analogs and their targets in place of this. The mechanistic explanation of renin is totally out of place here and I think you should replace the figure too. (Maybe a pymol figure showing a T.S.A. bound in the active site?)

Enzyme Mechanism: The section about enzymes should be related back to transition state analogs. The transition state structure section seems to be more in depth than in the actual transition state article so maybe it would be a good addition there; however, it currently doesn’t tie back to transition state analogs.

Examples of Transition State Analogue Design: I think your figure does a good job at illustrating the design of transition state analogs. You should try to tie your examples together with an introductory paragraph to this section and make sure each example adds to the narrative. The examples are informative but are currently just a collection of ideas rather than a story.

References: You have a good mix of references. Make sure to look up formatting for Wikipedia references to eliminate your duplicate references and have a common number each time the reference is used.

Overall you have added a great deal of information to this article. You need to work on tying this information together into a more cohesive story about transition state analogs, rather than a collection of ideas. Some of your paragraphs add knowledge to Wikipedia but do not necessarily fit in this article, at least without developing more narrative first.

UMMedChemStudent (talk) —Preceding undated comment added 02:55, 4 November 2013 (UTC)

Additional Comments

UMChemProfessor (talk) 01:50, 5 November 2013 (UTC) You've certainly added content to the site, but it does not flow into a smooth narrative, where each additional section contributes to the story in an additive fashion. For example, I'm not sure why there is a section on KIE and how that relates to transition state analogues. I agree with the reviewer that the intro should not include the renin example. Keep it simple for the audience and expand with examples later. I think a little more background on the examples is needed to fully understand them.

Suggestions from ChemLibrarian (talk) 15:30, 5 November 2013 (UTC)

1. As suggested by other reviewers, the size and locations of your images need work. See this page Wikipedia:Picture tutorial for how to place the image at different places and adjust the size.
2. Reference section should be called References not Reference List
3. I see some of your references are listed more than one time, e.g. 5-7 and 8-9. To fix it, at the first time you are citing it, give the reference a Ref Name. Your reference will look like "<ref name=Reference5>{{cite journal|last=Schramm|first=Vern L.|title=Transition States, Analogues, and Drug Development|journal=ACS Chemical Biology|date=21|year=2012|month=December|volume=8|page=71-81|doi=10.1021/cb300631k {{!}}}}</ref>" Next time, you need to use the same reference, just click on the Cite tool -->Named Reference and choose the reference name you need to cite again. Please let me know if you need further help.

Response to Reviewer #1

1.Wording of sentence in the introduction starting with “Interactions between an enzyme…” is worded in a strange way. Try and be clearer on what you are saying. Even just saying, “Enzymes interact with a substrate by means of strain or distortions, moving the substrate towards the transition state.” Or something like that.

I rephrased this sentence.

2. I would remove medicinal chemistry or drug discovery in the sentence starting with “Research in designing transition…”, or say it differently. Maybe say, “There has been much research in designing transition state analogs for drug discovery.” It seems to me that you do not need both mentioned in this sentence.

I removed the medicinal chemistry portion and reworded the sentence.

3. Any way to move the first figure down farther too where you are talking about Renin. I think it would be fine having the figure below the paragraph as well without text wrapping. 4. I think moving the second diagram over to the right hand side of the page would be helpful. 5. Can you find a reference talking about the “Lock and Key Model” or even a paper by Hermann Fischer talking about it for a reference? That might be hard to do but a textbook reference might work well here. 6. I believe that the Michaelis complex is also called an enzyme-substrate complex and in my experience that has been the more common term so it would be good to add that in as well. 7. The sentence beginning with, “Products are then released…” doesn’t seem to fit. It would sound better if you had a transition into this sentence such as, “After formation of the enzyme-substrate complex the product is released and the enzyme is again free to bind another substrate.”

The above sections were removed in general, so I did not need to make changes.

8. The first sentence in the transition state structure I would say backwards to the reactants or forward to the products. (A picture of an energy diagram could be helpful)

I reworded the sentence as well as added a diagram.

9. The sentence starting with, “Amino acids in an enzyme have…” mentions that the amino acids search for the transition state. Implying that they are searching for the transition state is saying that they are trying to get to that state and they will not be trying to get to a state of high energy, the enzyme and statistical mechanics is causing it to get to that state. 10. For the sentence starting with, “This slower time scale” I would again not say the enzyme is trying to find the correct alignment, it is taking longer because it needs to be oriented in the correct direction. 11. The last sentence in the first paragraph of Transition state structure again mentions finding and searching, I think you can use better words to describe this. 12. The next paragraph again used searching, the enzyme is in that set configuration due to probabilities not because it is trying to find that one state. 13. I think the last sentence of transition state structure could be worded better, “…amino acids, give enzymes their catalytic properties with high turnover numbers.“

I deleted these sections for simplification. 14. The first sentence for KIE, you should mention that you compare the rates of the isotopically labeled reactant against the more common natural substrate.

I reworded this sentence. Response 15-28

We think your comments on so many details on our article. In general, I modified every grammar error or the use of words you suggested. Although English is not my mother language I tried my best to rephrase what I have read in the literature. Thank you for your suggestions. I also added two figures in the next two examples which will make reader better understand the text in the example. In addition, all the figures are resized too 800px to 1000px depends on the original size I made. I also added all link that relevant to other wiki webpage. The reference format is modified with first author's first name and last name.

The followings are the responses I made in every comment you suggested:

15. First sentence of Determination of transition state architecture, “…structure of the enzyme of interest.” Could be worded better. Change one of the ofs.

I changed the sentence and change the section.

16. First sentence in second paragraph, “…elucidate the mechanism of action of enzymes.” Could be worded better. Change one of the ofs.

I changed the sentence and change the section.

17. Are there any words or ideas that can be hyperlinked to other Wikipedia articles in this section?

Yes, I added.

18. Second sentence in second paragraph has some grammatical errors say, “…which is fundamental to organic reactions. The molecular dynamic simulations provide…”

I've made some changes on this sentence.

19. Sentence starting with, “The complementary method would be…” would be best if it was reworded. Say, “The complementary method would combine molecular mechanics and quantum mechanics simulation methods. Also, what is the complementary method? Can you state why it is important to only treat the catalytic regions with quantum mechanics and the rest with molecular mechanics?

Because QM need a lot of computational time, it is not reasonable to treat whole system using quantum mechanics. In addition, only the cataleptics site is needed to simulate the chemical reaction and estimate the binding free energy. I think in this section, it is not necessary to discuss in detail. therefore I make a link to another wiki page.

20. Third diagram seem too large, having that smaller would be beneficial.

Yes, it is re-sized with 800px.

21. Singular plural mismatch when talking about methylthioadenosine nucleosidase. “…nucleosidase are enzymes that catalyze the hydrolytic…”

corrected

22. “Given the difference in distance between the N9 atom of…” Also, explain to us where the N9 atom is.

OK, I remove the N9 atom to Nitrogen atom. The diagram itself can explain the text.

23. Early and late dissociation stage, again explain that to us.

It is defined by the original author, which can be seen by the diagram. (same as 22)

24. “Based on the finding of different transition state structures, Schramm and coworkers…”

Thanks for the suggestion, I modified my original text.

25. Again explain what these binding affinity values mean to us and what was significant about them. What did it tell us?

I think binding affinity value just give the reader an impression that transition state analogues indeed has a strong binding affinity. I think it is not appropriate to discuss that pM is stronger than nM. So I make a link to "binding affinity". If reader is interested in it, they can just click on the link and see the meaning of the number.

26. For thermolysin inhibitor section the first sentence, “Thermolysin is an enzyme that catalyzes the hydrolysis of peptide amide bonds. The mechanism begins with…” You should be much clearer on the mechanism taking everyone through it one step at a time. Right now there are some grammatical errors and it is not very clear. A figure of the tetrahedral transition state would help.

Figure added.

27. For arginase inhibitor, “Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of…” The next few sentences are also unclear. Try going through the mechanism step by step and a diagram of the tetrahedral intermediate would be helpful.

Diagram added and explained.

28. Don’t mention the sulphonamide group unless you show a diagram of it.

Diagram added.

Response to Reviewer #2

Thank you for you kind suggestions. I totally agree with you that there should be a brief introduction in the example section to let readers better understand them. I think this also help the transition from the previous section. Or our article looks fragmented. In addition, I also made two more figures and I think readers will get more understanding about the other two examples. Some reference missing the first author's first and last name were also modified.

Response to UMChemProfessor

We change some sentence in the introduction to make it better understand, and we also remove the example in the beginning. To make it more smooth, I also combine the KIE part with QMMM methodology since they are both important for determining the transition state structure which is the main source of reference to design inhibitor. I uses some transmittal sentence to in link between each section with a short introduction in the last two sections. I also make two figures, to explain the last two examples which shows the enzymatic reaction and the intermediate. I think this is essential background regarding my topic. Therefore, I didn't write too much detain other aspect of the enzyme since the original wikipage has mention a lot. However, I add the disease related to the enzyme which may explain the motivation why we need to design the inhibitor for the enzyme. — Preceding unsigned comment added by Trcum (talk • contribs) 15:47, 10 November 2013 (UTC)

Response to ChemLibrarian

Thank you for your suggestions on the overall figure and reference format to make our wiki page looks better. I resized the all figures to 800px to 1000px according to the original figure I made. I set 1000px for the figure in the second example instead of 800px since the resolution looks best in 1000px. We also modified the references according to wiki format. All the duplicated references were also combined to one reference. — Preceding unsigned comment added by Trcum (talk • contribs) 15:59, 10 November 2013 (UTC)

I have left HTML-encoded comments in this article. To view them, click on "edit this page" when viewing substrate analog and look for the text between "<!--" and "-->"

From those comments:

"I created this page because there wasn't one before, and related pages

(enzyme, enzyme inhibitor, etc) focused almost exclusively on the medical applications of substrate-enzyme interaction. I wanted a page for generalized substrate analogs,

their common properties and applications, and I think this is a good start."

--Cis-domain