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Thank you for all your questions. Good luck for the test on Tuesday. Alison Hill

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Is C-OH a rotatable bond?

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Suitability of a compound as a drug candidate

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Suitability of a compound as a drug candidate

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When a questions asks us to explain our reasoning for a compound's suitability following a Lipinski's analysis, do we have to comment on other things or just regarding whether it passes or fails Lipinski?

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Good Morning,
Could you please confirm the number of rotatable bonds in chloramphenicol? Drugbank is stating 6, however, I can only count 3. Unless the bond to NO2 and OH also count and/or the chloroalkyl or alkyl alcohol but these look like terminal bonds to me?

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I was unable to attend the live session yesterday due to a medical appointment however I'm rewatching now, so sorry I couldn't ask this yesterday - when you say put your candidate number on each page do you mean our normal student number (9 digit one starting with a 6) or our exam candidate number (6 digit one)?

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Thank you for the clarification on isosteres  today! A question that came up for me was therefore: so can I make a note to myself when using isosteres to optimize the lead we use ones that retain most of that groups activity, slightly tweaking it (e.g. replacing a Cl with NO2, F and other EWGs to tweak activity) and when searching for the pharmacophore we are aiming to abolish activity of that group (e.g. replacing Cl with CH3/remove it completely to test for binding activity)?

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Could you please provide a model answer for this as we didn't go through it in the session?

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I am still confused as I thought C-N bonds did not count but we were counting them today?

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what would you call a molecule with the structure R-O-CH3?

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Is the C-O single bond between the C=O and O in an ester a rotatable bond or does this also have a high energy barrier like the C-N bond in amides?

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Are the questions for the CA test in the same style as the problem based questions from the formative problem sheets and the past exam papers? Will outside reading be required for the CA test?

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What is a bioisostere for an ester in a ring such as this one?

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In the book it says that when you P450 a methyl group, it gives CH2OH, and then subsequent reactions result in COOH. Are these reactions caused by P450 or are the subsequent reactions caused by alcohol DH and Aldehyde DH and do we need to say this? Also imagine a structure has 2 alcohols, can we identify both as different sites of metabolism?

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In questions where you want us to identify 4 possible sites of metabolism and for each site describe the reactions involved and identify the likely metabolites, do we have to give more than one reaction of each site of metabolism? Or is it like we did in synchronous session where you identify one site and give on example per site of a reaction that can occur there?

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When calculating MW for a molecule such as this one, do we include the HCl counterion in the MW calculation too?

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What's the difference between an isostere and a bioisostere?

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In q3 that you went through in the live session, why did you oxidise the alcohol to a ketone (what strategy in textbook does this come under i.e. simplification of structure, rigidification of structure, chain extension etc?) and also why did you remove the carbonyl from the amide group to make an amine?

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How would you answer part iv of this question?

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Is it possible to do one more example of identifying sites of metabolism and drawing the resulting structures?

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Question 1 - we didn't go over the answer to this in the week 2 live session and I was wondering whether there's anything you can do to the imine group to test whether that is the pharmacophore, other than replacing the N with an isostere?

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In q2 of the week 2 formative question sheet, for the amine group you suggest replacing it with an isostere or removing the ethyl groups. What does removing the ethyl groups do? Surely N would still be able to take part in hydrogen bonding if you're just removing the ethyl groups and converting R-N-Et2 to R-NH2? Could you instead convert the amine to an amide as in the lecture notes and the textbook?

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In the first part of the question you ask us to define the RO5, which does not include rotatable bonds (that is part of Veber's rules in the lecture notes). So in the next part of the question when you ask us whether certain molecules are suitable drug candidates, do we exclude rotatable bonds or include that in our working out?

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Does the sulfate group conjugated to an OH have one or two negatively charged Oxygen atoms in a phase II reaction? As in the week 1 solution sheet the sulfate has 2 negatively charged Os but in the slides it's marked as SO3-

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How would you answer part iii of this question to get full marks?

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metformin | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY In this example, it says that there are only 3 HBDs, however I counted 5 as I thought that for each NH2, you counted that as 2 HBDs as there are 2 NHs? *Edit. In fact, looking at multiple drugs, it seems that NH2 is always only counted as 1 HBD so have I just written this down wrong in my notes?

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When it says something like 'identify two or three likely products of metabolism', will you lose marks if you only put 2 products rather than 3 or will you get more marks if you put 3 products?

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This drug has 0 rotatable bonds, so does that mean that the C-N bond where the carbon has a double-bond to another nitrogen in this molecule doesn't count, and wouldn't in other molecules either?

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When I look up lisinopril (random drug to practice) on DrugBank, it says 12 rotatable bonds but I only identified 10 - can you please explain this in the session. I've also found that it differs between websites, e.g. guidetopharmacology.com says 13?

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Can you please go over the answers to question 2 of Week1's sheet, and question 4 of Week 2's sheet? Thank you.

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Will it be the usual download from exams ELE and upload to eBART?

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Is there a separate padlet for Dr Singleton? I can't find it anywhere

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When it says something like 'identify two or three likely products of metabolism', will you lose marks if you only put 2 products rather than 3 or will you get more marks if you put 3 products?

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Thoughts on the goverment delaying the second dose of the vaccine against WHO guidelines?

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If a patient had got no antibodies (ie you said the patients at St Thomas's had no antibodies after 10 days), how will the test work?

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IS the test actually being used widespread for patients now?

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In the discussion of the paper it states that the highest antibody titre was against N, why does this antigen produce higher antibody titres that the other antigens present on the virus ie S1, S2 or E?

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What is a two gate diagnostic accuracy study?

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How soon after infection do antibodies begin to appear? If someone got this antibody test a day after being infected could the test give a false negative result? Also how specific is the test - is it able to distinguish between different types of coronaviruses ie SARS and MERS? or may these produce false positives?

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How can light intensity change be used to measure the antibody present?

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What specifically is the difference between the antibodies used in the Rapid Test which recognise all human IgG, IgM and IgA and the antibodies used in the Antibody Class Differential Test which are specific to IgG, IgA and IgM?

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Why is a CRP sandwich assay used as part of the test?

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Will the antibody test still work in its current form with the new COVID mutations? If so, how much and in what way will the virus need to mutate for the test to no longer work?

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Will all the questions be problem based related to identifying modifications on structures and sites of metabolism, and also maths, or will some of the questions require short written answers in the style of the end of chapter questions in the textbook?

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Are you able to provide any further practice questions with answers for metabolism, pharmacophores and improvement of bioactivity related questions?

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How did government officials come up with the 10 or 14 day self-isolation period if you have a positive test. How can they know that someone will no longer be infectious after that length of time?

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This isn't a question specifically about Prof Shaw's antibody test but more generally about COVID tests, so I wonder if you or Prof Shaw would know the answer. I've heard of people getting a test and being told that their positive result is due to 'leftover' viral load from when they originally had COVID a few months ago and that it isn't classified as a positive test so they don't have to self-isolate etc. However if there is still viral load in their systems from initial infection several months ago then surely they are still infectious and could pass the virus on to other people?

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Do we need to have the document with QSAR data for all the different substituents up during the exam, or will the relevant ones be provided on the exam PDF? Thanks

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What does 9-dimensional measure mean?

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As there are 2 amino groups present, how do you ensure that amino acids react with the peptide tag/code and building blocks react with the target structure?

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To Rink or not to Rink that is the Question

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To Rink or not to Rink that is the Question

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At the end you mentioned this would not be in the CA test, only in the summer exam. Which lectures are assessed by the CA test? Is it L1-6, or 8?

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Is HIV/AIDS an epidemic or pandemic? In the lecture you refer to it as both

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How does the test differentiate between whether you've had COVID or whether you've just had the vaccine but not actually been infected with COVID?

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When you say the AZT trial to treat HIV/AIDS was halted after 16 weeks, was this because it was so good that they wanted to get it approved immediately rather than completing the trial?

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What value is considered to have biological activity?

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What is click chemistry?

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Why is the amine in the largest amount the best solution? Surely one of the amines in a smaller amount may be a more active drug?

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Please could you re-explain tagging, I don't really understand how it works

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If you're reacting with a family of acid chlorides, how will tagging with one amino acid tell you which acid chloride you have on each compound? How do you differentiate between the different compounds with different acid chlorides attached by using one amino acid tag?

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Is sequential release a step that follows recursive deconvolution or are they 2 different methods?

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Is there anyway to replace the amine group after reaction or is this resin a single use type?

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what do you mean by donating/withdrawing by resonance?

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For the last part of question 1 how many candidates do we have to suggest? Should it be one from each quadrant?

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Will people who get extra time in exams get extra time on the CA test?

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Hi on your quadratic help sheet it just says 'differentiate this equation' but in respect to which variable? Also I don't think the answer was correct as if all variables are being differentiated then the constants before sigma, logp and pi should all be added to give the +c.

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how do you know which sigma values to use with regards to their meta and para values?

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What is logA in the Hansch equation?

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In Q 3 (a) (A) I don't understand why NO2 is the best substituent rather than CF3?

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Why is it that the MR values for CF3 and CH3 are so similar?

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Why is K so much bigger for substituents in ortho position?

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When we calculate the log P of substituted compounds from log P of parent compound and the hydrophobic parameters of the substituents, why do we not take into account where the substituents are on the parent molecules? Why does this not matter?

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I was just wondering if you have access to the textbook answers online, as it says that these are restricted to the lecturers?

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How many questions will there be on the CA test in Feb?

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For Q 1.D E and F, I cannot see CN in the table?

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I am a bit confused as how you still move down the Topliss scheme even though only the 3-Br (out of 3-CF3 and 3-I) was found to be more reactive? Or does it not matter as long as one of the 3 analogues are more reactive to continue moving down the tree?

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Is KB the same as KX in the Hammett substituent constant equation?

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In the tutorial I think we capped the alcohol w/ a Me in Q2 to remove the HBD to identify the pharmacore. But why did we do this again in Q3?

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As a guide for such questions in the future, are esters a good functional group in terms of metabolism, pharmacophore identification and drug improvement?

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In molecule B, for the amine group could I have added LiAlH4 to make it R-CH2-NHR thus breaking the ketone?

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For molecule B, as one way to identify the pharmacophore could I substitute the hydroxyl group for a methyl group instead of turning it into an ether?

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Are we able to see answers for the problems we didn't go through in the live session?

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What is a pharmacophore triangle?

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In one of the problem questions it asks us to assess the different drugs capacity according to Lipinski and Veber's rules - are we expected to be know how to calculate the polar surface area of the molecule?

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What values above specified for rule of 5 are usually acceptable to pass?

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I am a bit confused by what you mean by the activity of anaesthetics is solely related to the log P value because there are no specific drug-receptor interactions, however some do bind receptors to work?

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Why and how is biological activity expressed as 1/C?

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Reduction of a carbonyl to an alcohol usually results in a racemic mixture formed. If the alcohol formed had opposite stereochemistry as the one shown on this slide, would it not still be able to hydrogen bond with the binding site? Therefore resulting in no reduction in biological activity when potentially there is?

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You mention that bulky aryl groups will have the same effect as hydrogenation of benzene to cyclohexane in decreasing hydrophobic interactions. How does this work?

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Through out the past few lectures in some examples you've presented a compound while saying we should already be familiar with it. However coming from MedSci we may have had less exposure to some of the mentioned drugs and their structure. Will there be any situation in which we will be expected to identify drugs purely from their structure under the expectation that we should already be aware as to their structure?

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As the goal is to increase polarity/water solubility to enhance excretion, why are there phase 2 reactions (e.g. methylation/acetylation) which decreases polarity and how common are these?

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I have had several emails from students about the problems I set yesterday so I thought it would be a good idea to remind people what these sessions are for and how I have chosen the material. We have not had an opportunity to have a 'tutorial' type session before and so I have chosen the parts of the MedChem course that students have found the most challenging over the years. As explained yesterday, we are used to students on the course coming from different backgrounds. You need to use the lecture material AND the relevant parts of the book. There is a LOT of detailed information in the text book (pp 168-176) on the reactions of metabolism and the products formed. For a 15 credit module it is expected that you study 10 hours per week (this includes the lecture material). If you look at the past exam papers, the MedChem part of the course is in Section B and you can see that Q3 has some essay style questions in it and Q4 is all problem solving. The MedChem CA test is designed to give you practice on the calculations and problem solving parts of the course before you do the exam. I have been teaching on this course for 15 years now and the students and myself always enjoy it tremendously. I hope you do as well. Alison Hill

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A methyl group is added to make the two rings co-planar. Would turning that junction into a third ring to connect them have the same effect? (Co-planar-wise, of course it would alter the electronegativity of the area, I was just wondering why a methyl group was used to stabilise it in this way). Thank you!

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Is there much difference between different editions of the textbook? I find it difficult to read online textbooks so would like to buy a copy but the older versions are significantly cheaper

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If it failed as anti-cancer drug in phase II due to side effects. Why is is in phase II again for Alzheimer’s, won't it still cause the same side effects?

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Did 1st pass metabolism mean that the drug is absorbed straight into the bloodstream?

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If P40s can oxidise both ortho and para positions, are there cases where it is preferable to only oxidise the para, or even just ortho, (such as steric hinderance), or are both positions always oxidised.
Thank you

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I'm assuming phase I and phase II reactions can happen in isolation (i.e a molecule may undergo just phase II reactions without phase I reactions and vice versa), am I correct?
Thank you