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What Would You Put In a Med-Chem Textbook?

I had an interesting note this morning from a reader who’s been asked about writing an introductory textbook on medicinal chemistry. He’s been looking over the field, and wondering what to include (and what to leave out). Quite a few current med-chem texts have a fairly robust section on combichem, for example, but many of these seem out of proportion to the technique’s current importance.
So what would you deemphasize if you were writing one of these? And what would you give more time to? (We’ll take the obligatory references to finding jobs in the field as already having been made!)

39 comments on “What Would You Put In a Med-Chem Textbook?”

  1. Anonymous BMS Researcher says:

    Perhaps at least as important as the specific technical details is to emphasize the complex tradeoffs inherent in medchem: potency, tox, ADME, PK, etc., mean you can rarely optimize one thing. For antivirals you also need to cover the spectrum of mutations found in clinical samples.
    So if you just focus on a single number (like EC50 or EC90), then you are likely to end up with potent compounds that have severe liabilities. You might not be able to fix those liabilities.
    I’m sure Derek knows this. Students might not, and they should.

  2. Fluorine Chemist says:

    Fluorine!!!!!!!!

  3. jrftzgb says:

    #1
    That’s the introductory chapter, most students are probably coming into this course with 2nd or 3rd year organic already, and a biochem, p chem as well, maybe a cell bio (my assumption). If you’ve got your basics you have to start on how all these fields come together, because that’s really what med chem is.
    I think you need a definition of what success is in a med chem laboratory, which brings up your next question. How do you define an ultimately successful medicinal chemistry research program? Is it a new drug? Is it a highly profitable drug?
    That might be your introduction what is success in med chem and what does it look like, then #1s suggestion is chapter 1, emphasizing how different med chem is in that it can’t be a completely reductionist process in the laboratory, this is really key in that it deviates from the way many people think about and teach science.

  4. partial agonist says:

    You need to clearly illustrate how medicinal chemistry is the central problem-solving tool of early drug discovery, and all of the facets of that this entails.
    Compound not potent enough? It is up to chemists to fix it.
    Not selective enough? It is up to chemists to fix it.
    Not water soluble enough? It is generally up to chemists to fix it.
    Too rapidly metabolized? It is up to chemists to fix it.
    Toxic compound or toxic metabolite? It is up to chemists to fix it.
    Not patentable? It is up to chemists to fix it.
    and more…
    Each of these types of problems should be illustrated, with the emphasis that potency is not very often one of the key issues to solve.
    I think you’d want to cover HTS strategies, PAINs, ligand efficiency and related parameters, Lipinski’s Ro5 and related metrics, fragment-based approaches, scaffold hopping, isosteres, solvation effects, and in a general way the principles of structure-based design.

  5. Electrochemist says:

    At least an appendix should talk about composition of matter patents, right-to-operate concepts, trade secrets and obviousness.

  6. JJ says:

    I’ve never known a medicinal chemist that couldn’t design and deliver potent compounds. What makes a med chemist a good med chemist is the ability to design and deliver drug-like compounds: potent compounds that also have the right physical properties, PK, ADME, tox, etc. Those are the things that young medicinal chemists need to be taught early on.

  7. Lyle Langley says:

    @#3…
    Each medicinal chemistry project would have different success parameters – not all are industry related either. For example, one can think about a medicinal chemistry project as developing a novel, selective in vivo tool compound that allows a target to be validated. I think the worst example of a medicinal chemistry success would be how profitable the drug is…that’s a sales success story. All we (as medicinal chemists) can do is provide quality compounds to our clinical colleagues. The rest is (mostly) out of our control since we cannot test on humans prior to the clinic. Another item to bring up to those wanting to be a medicinal chemist – develop thick skin. You will fail WAY more than you succeed, learn to take the successes (however small) and apply them to the project as a whole.

  8. Anonymous says:

    The need for a well run primary assay that doesn’t fluctuate too much, so you’re not second guessing if that point change did anything meaningful. This would be a good time to highlight the differences between enzymatic and whole cell assays.
    Also, in the introduction they should say you won’t be able to learn everything in a book but from your colleagues who have years of experience.

  9. John-john says:

    Don’t forget key references for farriers, ice-deliverymen, punkawallahs, bobbin boys, fendersmiths, telegraphists, and most importantly: pauper apprentices!

  10. jack says:

    Ch1. How to apply for unemployment.
    Ch2. How to update resume and network
    Ch3. Strategies in changing careers
    Ch4. How to explain to family members why you have so much education but have not worked in two years.
    Ch5. How to file for Bankruptcy

  11. Wavefunction says:

    Emphasizing the simultaneous multiparameter optimization problem – basically always having PK in mind even when you are optimizing potency – should always be a focus in a med chem textbook IMO.

  12. anonao says:

    Agree with #7. Success of the drug is not something that is entirely in the hand of a med chemist. If the biology hypothesis is wrong, then whatever someone does to a compound it’s not going to work, things in human can happen and can’t be predicted, the series may not be the right one (a good med chemist should be able to spot problems early and not just before clinical candidate stage)
    I think the goal is to deliver a compound that fits the best of what was asked up to animal model: safe and does something that’s supposed to do (already a big big task).

  13. Pessinist says:

    @8 g-d yes, (and if they include this send me a copy to include in the handout for ‘cell-to-animal pathway focused PI’s’ on how thinks work)
    For the nascent author: think about a chapter or two at the end on what to expect from some of the associated fields. Common techniques w/ what they do and can’t inform (is what is believable vrs full-of-it from paper/speakers/colabs). Cell/animal assays in general, HTS, comp. chem.

  14. @countthebricks says:

    How about the use of different software packages? The technology is going to continue to advance but there have to be some that are core to the field.

  15. entropyGain says:

    How to play nice with others (biologists, preclinical, process).
    Project management 101 as a pre-req.

  16. Anonymous says:

    de-emphasize on in vitro potency, more emphasis on physiochemical properties influences on ADME/PK

  17. CMCguy says:

    I think there would be value in providing a solid overview of the entire drug development process to help med chemists better appreciate they are part of a huge effort required bring a drug to market. Two areas within that I would emphasis are regarding the ultimate mission is to treat patients and then the value of interactions with process types (plus formulations) during and post-discovery efforts as even though the focus changes in development there are sometimes things the medchemists can do during the design stages to ease the paths forward (e.g. chemistry and molecule-wise and properties that influence PK ADME etc.).

  18. An Old Chemist says:

    Derek, nothing beats including case histories of a few drugs, especially the ones that were made by logical thinking, e.g. beta blockers and cimetidine (Sir Blacke, the SKB’s Nobel laureate). These should be written by med chems who worked on them for decades. This should be in line with the series of books ‘strategies and tactics in organic synthesis.’ This should include even tiny details.

  19. MAZ says:

    Now, while we are waiting for this book to be written, is there an existing introductory textbook on this topic that you would endorse without reservations?

  20. milkshake says:

    I would definitely include a chapter about limitations and pitfalls of HTS (and in vitro testing in general), and include examples of good (and bad) crystallography-based design

  21. annon says:

    Wow…aren’t there enough already?

  22. KissTheChemist says:

    From experience, I’ve always enjoyed the case studies (what went right, what went wrong, how we fixed it). In the real world, problem solving is the key, and as many have already said its multi-parameter fixing too!

  23. Organic Chemist says:

    When I was new to the field, I looked for a textbook explaining the basics and never found a good one. A lot of things Medicinal Chemists know from experience and are kind of obvious to them, for example what kind of substructures to avoid if you don’t want metabolic trouble, what features to add to improve solubility etc.
    But as a newbie in the field, you don’t know these things.
    Most of the Med Chem text books use a lot of complex examples from drug discovery programs to explain the various strategies. However, in the beginning, a simple table or list kind of thing with “does and don’ts” in Med Chem would have been really helpful.

  24. Anonymous says:

    I would show a few informative charts, for example:
    1. Increasing number of job cuts in med chem vs time
    2. Incresing % of med chem work outsourced to China
    3. % of med chemists in long-term unemployment
    4. Suicide rate of med chemists

  25. Perry says:

    I had an interesting note this morning from a reader who’s been asked about writing an introductory textbook on medicinal chemistry. He’s been looking over the field, and wondering what to include (and what to leave out).
    The two sentences above are very strange. Why was this individual asked to write a book on a topic where he does not have the judgement to select the appropriate scope? Perhaps he should refrain from accepting the job.

  26. great unknown says:

    Reading #25 brings to mind important, often overlooked topics: honesty, good judgement, and the consequences of the failure thereof.

  27. TX raven says:

    @24
    Have you got any data on your bullet 4?

  28. Christophe Verlinde says:

    “The Practice of Medicinal Chemistry” edited by C. Wermuth is probably one of the best books out there.

  29. Anders says:

    Dont forget peptides, peptidomimetics and biologics in that book – a growing area and within the med chem umbrella.
    also fragments (vs HTS) is essential

  30. Deselected in NC says:

    Chapter 1. How to make an antibody

  31. Anonymous says:

    Chapter 1. The history of medicinal chemistry
    The end

  32. Anonymous says:

    Discussion of what a CRO is and how they work with big pharma companies would be useful. It is more likely that a kid taking a medchem course today will be involved in directing the activities of a CRO rather than actually doing hands-on synthesis.

  33. A. River says:

    Maybe a small handkerchief to dry all the commenters’ tears?

  34. An Old Chemist says:

    Clever strategies on how to force your name on other’s discoveries, especially when your smart colleagues are from non-English speaking foreign countries.
    Clever strategies on how to become a manager quickly, over-stepping your smarter non-English speaking foreign-born colleagues.
    Strategies on the use of buzzwords before MBA management audience that will get you quickly rising on the management ladder leaving your smarter foreign-born colleagues on the bench.

  35. Design Monkey says:

    A chapter with rule-of-thumb cookbook recipes (Topliss schemes and like), drawn as flowcharts for dummies, with thorough emphasis that goal of synthesizing compounds is to get INFORMATION.
    Because, really, it is freaky to see, how senior chemists-project leaders, when left to their own devices, promptly go methyl, ethyl, butyl, futile road.

  36. Yancey Ward says:

    I find myself sympathetic to Jack’s list, but then I am deeply cynical about the field’s future.

  37. newnickname says:

    The TOC of Burger’s Medicinal Chemistry, 7th Ed, 8 Volumes, 6416 pages is available free on the Wiley description page:
    http://www.wiley.com/ WileyCDA/ WileyTitle/
    productCd-0470278153.html
    For an Intro book, you can scratch off a whole lot of stuff. On the other hand, you can also pick out some pretty essential topics you’d want to cover, even if not as a complete chapter unto itself.
    One principle that I think could stand being stated with emphasis: FOLLOW THE DATA!

  38. Joh says:

    Derek—
    On Christmas night, having exchanged gifts with my best friends, I came home, retrieved my refrigerated bottle of Japanese plum wine (fabulous!), cranked up my Mac, and looked up chlorine trifluoride online for the nth time, just for laughs. Naturally, I ran across your blog and re-read your acerbic comments on this most malevolent of compounds. Did we really create something that will set ASBESTOS on fire?!?Perhaps coincidentally, I am currently reading Richard Rhodes’ captivating book, “The Making of the Atomic Bomb.” It occurred to me: what if the Nazis, following Ruff and Krug’s original synthesis of ClF3, had actually found a way to successfully weaponize this demonic stuff and, say, spray in on the troops landing at Normandy? Imagine the average solider’s thoughts: “Okay, I can handle being shot in the head, but being DISSOLVED in a burst of flame??? No way, Jose. Get me OUTTA here!!!” We might all be speaking German now…
    Mit freundlichen Gruessen und vielen Dank,
    John “Almost-a-Chemist” Calhoun,
    Fort Collins, CO

  39. John says:

    I think de-emphasizing combichem is generally a good idea. I also think an intro text should cover it all slightly. So we should have chapters on the biological requirements, physical requirements, potency requirements, discussions on target selection, and then case studies showing the process-from med chem through the biology and I would make sure to include some process chem stuff too as the vast majority of undergrad students will not see this in any other course. So- from target selection and validation through to handing off for phase three…I think an intro text should be designed to give a general overview of the field and give examples. It is not going to be a bench reference for the working med chemist (I never look at my intro to med chem text anymore though it is just over on my shelf).

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