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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Oxford's New Building, One Year Later | Main | Honesty, Of A Sort »

January 19, 2010

What Should Non-Chemists Know About Medicinal Chemistry, Anyway?

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Posted by Derek

It's been a busy day on the front lines of science around here; apologies for not getting anything up until now. Here's a topic that I was discussing with some colleagues not too long ago: how much do we need to know about each other's specialties, anyway? I'm assuming that the answer is "more than nothing", although if someone wants to make the zilch case, I'd be interested in hearing it done.

But once past that, what's the optimum? I (for example) have never done cell culture. Nor do I see myself ever needing to do it (and anyone who needs me to is clearly in a bad way). I know the broad outlines of the field, but almost none of the details, and I'm sure that even my broad outlines have some faint parts in them. So if I'm at some sort of meeting where the problem-of-the-day turns on cell culture issues, I can be of no help at all. Is this a problem? I understand that different cells take to culture conditions differently, have varying growth rates, need media changes and whatnot, can generally only be passaged a certain number of times, etc. In short, I know roughly what to expect from my cell culture colleagues, and what would be silly of me to demand. Is that about right?

After all, I don't expect them to know the ins and outs of medicinal chemistry, particularly the synthetic organic lab part of it. Things like methylene chloride being rather more weirdly polar as a solvent than you'd expect, or the fact that some amines will stick to solid magnesium sulfate drying agent (but not sodium sulfate), or how you can azeotrope out acetic acid with toluene, or how you want palladium tetrakis to be lemon yellow and not orange - these and dozens of others are the tricks of my lab trade, and they don't know mine in the same way that I don't know theirs.

But I do like it when my biology colleagues have the broad outlines - that molecules with chiral centers, other things being equal, are often harder to make than achiral structures, that sticking a lot of cycloalkyl grease on a molecule is asking for metabolic trouble (no matter what it does for the potency in the assays), what sorts of things tend to make a molecule more (or less) soluble, and so on. Those are the equivalent of me knowing that primary cell lines lose some of their functions in culture, the difference between transient transfection and a stable cell line, etc.

It seems to me that each discipline in our business could draw up a list of What Everyone Else In the Company Should Know about their area. So, to start off with, I'm throwing the comments section over to what biologists (and others) should know, at a minimum, about med-chem. Take it away!

Comments (35) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. goldilocks on January 19, 2010 1:53 PM writes...

ChemDraw structures are two dimensional representations of three dimensional structures... and bonds can rotate. Seems like something the biologists should know, and yet so many of them seem to forget.

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2. PharmaHeretic on January 19, 2010 2:03 PM writes...

Usually 3rd year organic chemistry (undergrad) is enough, IF they had understood the material. I do not claim to understand 200 reactions, but can follow the logic behind a well written synthetic scheme and have a rough idea about what it can and cannot do- substitution wise.

I suggest carefully rereading an undergrad organic chemistry textbook, and using scifinder to see what others have done.

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3. Ed on January 19, 2010 2:40 PM writes...

Hey! Cycloalkyl grease is what we're all about at our shop - preferably with a hydroxamic acid attached!

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4. Anonymous on January 19, 2010 2:53 PM writes...

You may find this paper interesting for the purpose of this post.

http://dx.doi.org/10.1016/j.drudis.2009.04.005

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5. qetzal on January 19, 2010 2:56 PM writes...

PharmaHeretic -

By "3rd year organic chemistry" you mean the two semesters of OChem that a biol major would typically take during their 3rd (junior) year, right? Cause if we biologists need 3 years of OChem to understand What Everyone Should Know about med chem, we're doomed!

;-)

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6. Phillip Chase on January 19, 2010 3:37 PM writes...

OK, here's some things straight off the top of my head to move things along:

Know if they use up all the material, they understand how long it may take to make more.

Potency is usually the easiest parameter to optimize; all the others (permeability, metabolic stability, toxicity, solubility, crystallinity, etc.) are increasingly difficult to modulate in concert with the others, and sometimes by themselves.

Precision for the in vitro assays is more important than accuracy when you're looking for the effects of structural variation.

Don't worry about asking for more compound to do critical experiments; making the compounds should not be the limiting factor in progressing the project (although it many times is).

Know the difference between enaniomers, diastereomers, and what a straight racemic line in ChemDraw means in relation to a front or back (up or down) line.

That there are issues of scale when making 20 g of something you've only made in a 30 mg amount once.

Understand what types of functional groups impart what types of effects, e.g. polar for solubility, H-bonding, etc.

Understand the concept of conformational restriction and why it can impart a positive or negative effect on activity.

Understand where diversity is useful and where it is not. This is critical when assay throughput and turnaround or chemistry productivity comes up, so it's a productive conversation instead of one group automatically taking up a defensive position.

That sometimes doing med chem is just trying out a lot of different ideas, with what appears to be and many times is randomness; if it was that easy to design a drug from scratch, we wouldn't need hundreds of us in a company to do it.

Understand the concept of isosteric replacements.

Understand the difference between sterics and electronics.

Know what x-ray structural info and computational chem can provide.

Understand that we usually can't tell a priori what level of solubility a compound is going to have in a DMSO/buffer system.

Understand that we usually have more ideas than we can synthesize and must use experience, knowledge, logic, colleagues, and even management to try to triage down to the best and practical ones.

Sometimes the "obvious" compounds to make turn out to be incredibly difficult to synthesize.

Understand the concept of patentable space and why some leads are not followed further.

Understand the concept of flat SAR.

Back to work; hopefully more to come...

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7. JK on January 19, 2010 3:41 PM writes...

Dear Phillip

Just make the damn cmpds and shut up. please.

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8. PharmaHeretic on January 19, 2010 4:00 PM writes...

qetzal,

Yes, I am talking about organic chemistry as taught to a biochem-type major. However, most universities do a poor job of teaching the material and high school does not prepare students for university.

I would suggest reading, and understanding, an undergrad-level organic chemistry textbook.

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9. CVL on January 19, 2010 5:11 PM writes...

PharmaHeretic,

I am with qetzal and Phil on this topic. I've feel that I probably did learn that 1 year of ochem and I feel that my university did a pretty decent job of teaching it to me. But even then, there are clear gaps in my knowledge. Somethings I probably should know like the differences between chiral and achiral chemistry. But I have no clue how sticking on specific functional groups are related to the permeability. Just like in cell culture, most of these things aren't taught but rather they are picked up from years of experience. No textbook tells you that MCF7 cells grow faster than CHO cells and no textbook should.

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10. Simon on January 19, 2010 7:53 PM writes...

Just want to chime in and let you know that your problem is not limited to medicinal chemistry, or even biology.

Us telecommunications designers have the same problem. Shall we have lunch? ;-)

(Yes, that's right, I only have high school chemistry - my training is in electronics & software - but I'm fascinated by hard science & tech in general so I do read this blog).

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11. barry on January 19, 2010 8:35 PM writes...

recognizing that the gram of drug substance that has been used for milling/formulation studies can usually be repurifed far faster than another half gram can be synthesized would be a welcome leap in sophistication.

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12. anon on January 19, 2010 9:54 PM writes...

#7:

Jeffrey Kindler - is that you?

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13. Old-Timey on January 19, 2010 10:07 PM writes...

Can we include the computational chemists in with the "non-chemists"? I recently had to explain atropisomerism to a PhD computer-jock chemist.

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14. Old BioChemist on January 19, 2010 10:40 PM writes...

It is clear that both sides have some learning to do. In my experience, having open, collaborative, interdisciplinary project discussions enlighten all involved and make better scientists. It takes time to understand the limitations of each discipline.

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15. anon the II on January 19, 2010 11:19 PM writes...

Old-Timey, I confess.

I've made them, I can assign their configuration using the Cahn-Prelog-Ingold rules and I've known about them since reading Eliel's book 33 years ago, but I still had to look up atropisomers to remind myself just what the term meant.

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16. Curt Fischer on January 20, 2010 2:35 AM writes...

A good follow-up to this post is the converse: what do medicinal chemists know about, say, cell culture? I'd start off, but I'm not a medicinal chemist.

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17. London Chemist on January 20, 2010 3:20 AM writes...

Two things I have trouble explaining to biologists (or they have trouble understanding?):

1)The difference between kinetic and thermodynamic solubility, and why in house synthesised batches are less soluble than the 2mgs bought from ACME chemicals...

2) How much custom syntheses cost. If Sigma sells stuff for less than GBP100 (USD160), how come 50mg of that active cpd from the lit with 3 chiral centres costs over GBP10K (USD16k)....

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18. DrSnowboard on January 20, 2010 4:43 AM writes...

"That sometimes doing med chem is just trying out a lot of different ideas, with what appears to be and many times is randomness; if it was that easy to design a drug from scratch, we wouldn't need hundreds of us in a company to do it."

Stone the heretic, he doth blaspheme the gods of rational drug design. Stone him.

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19. Jon-ster on January 20, 2010 6:42 AM writes...

Off-topic...but I find that cyclohexane is a much better azeotrope for acetic acid than toluene, and the azetrope distills at lower temperature. Just one to keep in mind!

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20. Mark on January 20, 2010 7:37 AM writes...

As a pharmacologist, it's been very helpful to understand that gram scale material doesn't just appear overnight, and that formulating for in vivo studies can be tricky as well.

Conversely, chemists should understand the inherent imprecision with biological assays. As the saw goes, physics goes to five decimal points, chemistry to the decimal point, and biologists are lucky to get the sign right

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21. anchor on January 20, 2010 8:13 AM writes...

My experience is that it is easier for medicinal chemist (starting of as organic chemist) to become biologist, rather than other way around. In my group meetings I always found constructive suggestions on biology coming from medicinal/organic chemist. To me the organic chemistry is like math in that you know good math then you can be great physicst.

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22. biochem belle on January 20, 2010 8:38 AM writes...

From someone who is somewhere between biology and chemistry...

Biologists don't have to understand all the chemistry required to make a compound but should be able to follow enough to know where substitutions can be made most readily. This might be as much an issue of communication b/t med chemists and biologists as it is biologists not understanding chemistry.

Biologists should know what functional groups are bad news from the standpoint of solubility and metabolism and why certain substitutions (like chloro- for methyl) are made.

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23. kate on January 20, 2010 8:53 AM writes...

An interesting point that we have recently been discussing too! There was a good paper recently in Drug Discovery Today, from the chemists at Vernalis in the UK, who have clearly decided that enough is enough and have educated their biologists...
doi:10.1016/j.physletb.2003.10.071

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24. HappyDog on January 20, 2010 9:16 AM writes...

#13 Old-Timey

Please realize that there is a great diversity in the backgrounds of computational chemists / molecular modelers. There was a joke at one company I worked at that none of us were qualified for our jobs because no one had a degree in computational chemistry. Most comp. chemists actually have backgrounds in a different field such as medicinal chemistry, biology, biochemistry, computer science, mathematics, physics, pharmacology, etc. So I am not necessarily surprised that you could stump an individual comp. chemist with a question like that, but on the other hand, I've known very good comp. chemists with many years of med. chem. experience before they stepped out of a lab who have a really good idea about what compounds are synthetically accessible. They might not be good protein modelers however, but we have other computational chemists that do that well. Most of us are good at scripting (Perl, Python, C-shell, etc.), but aren't good programmers. On the other hand, there are very good programmers who don't understand cheminformatics . . . The point is that our field is actually a pretty diverse one.

I have one request for something chemists should know about chemistry. Namely, tautomers, resonance structures, and protonation states.

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25. goldilocks on January 20, 2010 9:22 AM writes...

As #16 said, there are things that chemists should know, too... anyone want to volunteer?

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26. E on January 20, 2010 11:54 AM writes...

To Anonymous #4, many thanks for posting a link to the Drug Discovery paper! I've now sent that paper to all of my colleagues (12) in my regulatory toxicology department and have already had a lot of them say it was just what they'd been looking for without success.

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27. HappyDog on January 20, 2010 11:56 AM writes...

Could I make a comment about what med. chemists should teach us comp. chemists?
1) What chemistries are obviously disallowed. Examples include connections through O-O bonds and reactive groups like Michael acceptors. There's a list of chemotypes most med. chemists won't touch. It would be extremely useful to distill it down for us.
2) The key synthetic steps for a chemical series in a given program, as well as common chemical reactions in the company and the industry as a whole. It's been my experience that on a program, there are perhaps six key synthetic reactions that take place. It's useful information since this often defines the sorts of chemical matter that can be purchased and therefore what compounds are readily accessible. Also, some reactions seem to be highly favored within a given company / department but may not be widely used outside (e.g. Weinreb amides). Others, such as the ubiquitous Suzuki coupling, are common throughout the industry.

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28. mad on January 20, 2010 12:19 PM writes...

The most important think really is that they actualy talk to each other. Understanding would be "better" but is secondary to getting the correct information from the expert.

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29. AJ on January 21, 2010 3:56 AM writes...

Furstly, thanks to those who have made positive commetns about our DDT article; it's good to know our efforts are helpful.

I thougt it might be worth noting how the article itself arose. Over several discussions, we realised that our colleagues looked at, and discussed, compounds from Med Chem in very different ways. Where we saw atoms, reactive centres and functional groups our comp chemists saw electrostatics and hydrophobes, our crystallographers saw electron densities and our biologists saw "ringy things with sticky out bits" (Thanks Mrs W, you know who you are!!).

We jointly realised there was a need for a common terminology if we were going to work together better. But rather than, as Kate notes above, having "clearly decided that enough is enough and have educated their biologists...", this content was developed primarily by our colleagues. We didn't ask ourselves what they should know, we gave them ownership and asked them to tell us what they felt they wanted to know. The manuscript is the summary of these discussions, and pulls together thier suggestions as to what they would find most useful.

We hope it serves it's purpose, and would encourage others to do similar!

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30. Another Simon on January 21, 2010 6:29 AM writes...

@1, there's an old saw in comp-chem that chemists don't think in 3D, they think in 2D. I guess everyone goes around assuming the other guy thinks the world is flat.

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31. Design Monkey on January 21, 2010 8:57 AM writes...

Rule Nr.1. in dealing with biologists.

Making a gram of compound at once tends to be easier than 50mg + 50mg (three months later) + 100mg (yet a month later) ...

If the biologist asks for the compound for the second time - make (way) more than he asks.

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32. JJM on January 21, 2010 12:57 PM writes...

@21. anchor "My experience is that it is easier for medicinal chemist (starting of as organic chemist) to become biologist, rather than other way around."

I don't know whence you came by that information; but it is generally untrue. Biology is more complex than chemistry in that the foundations lie in statistical trends from difficult-to-control experiments.

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33. Eli Rabett on January 23, 2010 10:23 AM writes...

The one thing you need to know is how to find someone who knows. Among other things that means you have to learn enough to meaningfully state your question

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34. Betsy on January 25, 2010 12:51 PM writes...

I am a biologist at a small drug discovery company. I came here straight from an academic postdoc, and had not thought much about chemistry since undergrad. I've caught up a bit since then, but still should probably know more about chemistry than I do.

But I have to admit, I get a little irritated when our chemists expect us remember what every single compound looks like, and to contribute to SAR analysis. There are FAR more chemists here than biologists, and I've got my plate full trying to design and run assays for 3 different projects, now I have to think like a chemist too? Come on.

I have enjoyed seeing your comments about what we biologists should know--some of that is valid, particularly how long it takes to do things, and what the limitations are on compounds that you can make.

However, it goes both ways. I would like chemists to understand how cell culture works; that I can't have that experiment done this week because I haven't thawed the cells from the liquid nitrogen yet. I would like them to understand that sometimes assays just don't work--we don't always understand why, but we will try to fix it. Sometimes the biology of what we're doing isn't completely understood, so if that experiment didn't turn out the way you wanted it to, it may not be my fault. Biology is less predictable/controllable than chemistry--we have adapted to this, many chemists have not.

A few years ago, I proposed that we should have a "Freaky Friday" day a couple of times a year. Have one of the chemists follow me around for a day, so they can see what we actually do, and how long it takes to do our experiments. Similarly, we could shadow them, to better understand what they deal with on an average day. No one has taken me up on it so far.

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35. z1 on April 25, 2013 2:09 AM writes...

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