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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: Twitter: Dereklowe

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November 12, 2007

Here Be Chiral Dragons, With Fluorinated Fangs

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Posted by Derek

There’s a saying that you see attributed to all sorts of old humorists, which goes something like “It’s not the things you don’t know that get you, it’s the things you know that just aren’t so”. (I always put it down to Kin Hubbard, but the best case can probably be made for Josh Billings). What you can’t argue about is the truth of the thing, and that truth gets demonstrated at all phases of a drug discovery project.

You see it all the time in the med-chem labs, that’s for sure. After a project has been going a while, a lot of people have had a crack at the SAR, and have made a lot of different compounds. Everyone has put their own facorite groups on, and things have been tried out on all the reasonably accessible parts of the structure. That’s when the myth-making starts – I’ve never been on a project where it didn’t.

“Trifluoromethyl in the 4-position’s a killer – I wouldn’t put anything electron-withdrawing there if I were you”. “You need the R stereochemistry at the benzylic site; those always work better than the S”. “Somebody tried to make the meta-substituted compound – it never worked.” “All the methyl compounds get cleared faster than the fluoros”. This sort of things will sound very familiar indeed to my drug-discovery readers. Anyone who joins a project that’s been going for a few months or more will get all the folk wisdom of this sort that they can stand.

But how much of it is real? In my experience, about half, and sometimes less. Many of these rules of thumb are born from only one or two examples, often as not from the earlier days of the project when other parts of the structure were different. It’s a rare project where you can mix and match with impunity, which means that these rules often outlive their validity. You really have to go back and check up on these things. And sometimes, disturbingly, there’s no foundation at all. This is a real danger in a long-running project with a lot of manpower changes and a long list of compounds. Once in a while you see everyone convinced of something that has no empirical support at all – it’s just something that “everyone knows”. Making compounds to put such superstitions to the test should be actively encouraged.

But depending on the culture of your company, or just your project team, that’s not always easy. Some project leaders ask for (or at least tolerate) a certain percentage of let’s-find-out compounds, which I think is healthy. But in other shops you have to brave well-meant ridicule or outright hostility when you send in analogs that challenge the accepted wisdom. As usual, it’s a question of the odds. If you make nothing but contrarian compounds, you’ll have a lower hit rate than the folks who are following up on the current leads. But if all you do is follow up on the current leads, never looking back or to either side, you’ll miss out on a lot of potentially useful things. Moderation in all things, the man said.

Comments (20) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs


1. milkshake on November 12, 2007 10:06 PM writes...

That's why you need a losely-supervised a mix of people with varying levels of experience (and prejudice) and a boss that is not too dogmatic about things. I have been couple times shaking my head in disbelief about my colleagues "you are making - what?" only to be surprised when a good compound that should not be came out of the series.

Just recently we had a moment when the dogma "we know for *years* that this side-chain needs to be..." has fallen. (Now we can say on a meeting that we have two good lead structures - and pretend as if everything was done with the rational design).

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2. SRC on November 12, 2007 10:16 PM writes...

Good post. I've previously found that widespread conclusions have been based on exclusion of data implying the opposite, on the grounds that "something must be wrong" with those data. ("Circular reasoning," see "Reasoning, circular").

More pragmatically, if less alarmingly, synthesizing inactive compounds helps to define patent claims more precisely, a little-appreciated but valuable contribution.

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3. anon on November 13, 2007 3:58 AM writes...

"You really have to go back and check up on these things. And sometimes, disturbingly, there’s no foundation at all. This is a real danger in a long-running project with a lot of manpower changes and a long list of compounds."

A lot of information in a project is 'lore'. It is there but in peoples heads or in footnotes of reports, or contrived sentences in reports (done this way 'cos the view was controversial at the time). Anyway, the point is that time is never allocated to have in house project written reviews where all the project reports are pulled together, competing hypotheses are outlined and discussed etc ... However, time is allocated so that people read SOP (standard operating procedures) for such things as, 'how to use a hotplate' etc.

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4. emjeff on November 13, 2007 8:05 AM writes...

“It’s not the things you don’t know that get you, it’s the things you know that just aren’t so”.

I'm pretty sure Will Rogers said this. attributes this to good ol' Will.

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5. tom bartlett on November 13, 2007 9:52 AM writes...

Stretch out your brain before coming to work in the morning. What hasn't been done on the scaffold? WHY hasn't it been done?

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6. WC on November 13, 2007 11:22 AM writes...

"Once in a while you see everyone convinced of something that has no empirical support at all it's just something that "everyone knows"."

I've seen this too many times. Someone puts a conclusion in a powerpoint slide and it becomes a fact without much further debate. This kind of laziness was common at my previous employer. They ultimately failed. I think there's a lesson there.

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7. DrSnowboard on November 13, 2007 11:48 AM writes...

But all drug discovery is random, it just looks ordered because you don't know everything about everything...

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8. Norbert on November 13, 2007 12:00 PM writes...

The controversy over the origin of the quote in question is a self-referential example of at least some published sources knowing what ain't so. The Quote Verifier gives the nod to Josh Billings, who died in 1885; the great Will Rogers was born in 1879.

“It AIN’T so much the things we don’t know that get us into trouble. It’s the things we know that just ain’t so.” In various forms this popular observation gets attributed most often to Mark Twain, as well as to his fellow humorists Artemus Ward, Kin Hubbard, and Will Rogers. Others to whom it’s been credited include inventor Charles Kettering, pianist Eubie Blake, and—by Al Gore—baseball player Yogi Berra. Twain did once observe, “It isn’t so astonishing the things that I can remember, as the number of things I can remember that aren’t so,” but biographer Albert Bigelow Paine said he was paraphrasing a remark by humorist Josh Billings. (In Following the Equator Twain also wrote, “Yet it was the schoolboy who said, ‘Faith is believing what you know ain’t so.’”) Billings, whose real name was Henry Wheeler Shaw, repeated this theme often in different forms. On one occasion Billings wrote, “I honestly beleave it iz better tew know nothing than two know what ain’t so.” A handbill for one of his lectures included the line “It iz better to kno less than to kno so much that ain’t so.” Across this handbill Billings wrote longhand, “You’d better not kno so much than know so many things that ain’t so.” Apparently the humorist considered this his signature “affurism.”

Verdict: Credit Josh Billings.

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9. SP on November 13, 2007 12:07 PM writes...

Is there a good resource (book, web site) for med chem? In grad school we had biochemistry and organic stereoelectronics and multistep synthesis, but nothing about drug design. Thiophene as a phenyl isostere, triazoles as an uncharged version of a carboxyllic acid, what groups to avoid (which you've mentioned before), etc. All these things have been learned on the fly- I'm not a medicinal chemist, I just pick up what they say in meetings, so my knowledge is patchy and probably has many incorrect bits.

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10. Wavefunction on November 13, 2007 12:07 PM writes...

Did you base the saying on a review on VS by Brian Shoichet?

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11. tom bartlett on November 13, 2007 12:19 PM writes...

"But all drug discovery is random, it just looks ordered because you don't know everything about everything..."

It's not "random" in the least.

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12. MolecularGeek on November 13, 2007 1:14 PM writes...

Would you settle for stochastic? *grin*


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13. tom bartlett on November 13, 2007 1:44 PM writes...

"Would you settle for stochastic? *grin*


That's closer; to be sure, there's rarely one "correct" solution to any drug discovery process.

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14. Jose on November 13, 2007 5:09 PM writes...

I have to wholly agree with Dr.Snowbrd. Random (in a defined space) it is. Wouldn't it be fascinating to give 5 companies the same kinase hit, and ask them all to analog it against kinase X, and then track the evolution of series? After 6 months the leads would look pretty divergent, and after 18-24 months, I suspect most (if not all) would be essentially unrecognizable. SAR hunches are not logical or orderly (good for our continued employment!)

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15. CMC guy on November 13, 2007 6:21 PM writes...

Well stated is the need for moderation or a good balance is key component as arguments can be made on both sides. Expertise and Intuition seem to increase with experience and thus as knowledge gained interpretation faster and better. However getting too trapped in past thinking, implicit rules or ingrained lore (particularly when so often based on limited or nonsequator data) will create blind spots to what could be important and dissuade pursuits. Innovative inspiration and daring to travel upstream should be part of scientific endeavors although can be tougher to sell, particularly in a logic based or bottom-line environment. At the same time investigations without context or guidance can also lead to compounds which can not advance. Individuals that can operate well in the full spectrum of Innovation/Expertise are rare and perhaps can be found in collective per comment 1 (Derek weren’t you going to at some point make a list of characteristics for discovery personnel?).

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16. Great Molecular Crapshoot on November 13, 2007 6:27 PM writes...

Project and medchem folklore should be continually challenged. SAR-space is non-linear and unevenly filled. Local patterns are usually more informative than global trends which are typically weak. The most interesting SAR is when small changes in structure lead to large changes in activity. One view of QSAR is that its funtion is not to predict but to reveal outliers. Beware of quantitative models with large numbers of descriptors for they are a certain path to ruin.

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17. Caleb on November 13, 2007 7:12 PM writes...

You could try Silverman's "The Organic Chemistry of Drug Design and Drug Action." I used it for my medchem class in grad school and it's a great reference.

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18. Polymer Bound on November 13, 2007 10:26 PM writes...

Save your money on textbooks and start reading primary lit.

Totally Medicinal has a great list of papers med chemists should read.

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19. MolecularGeek on November 14, 2007 7:26 AM writes...

Personally, I prefer Patrick's "Introduction to Medicinal Chemistry" over Silverman. They are both targeted at the senior undergraduate/graduate first course level, but I find Patrick to be much more readable. Silverman does go into detail on more mechanistic details, but if you are already a qualified organiker, most of those will already be relatively clear. Where I think Patrick wins is in being more liberal with discussions of tools and techniques medicinal chemistry uses, and in offering a better selection of case studies in actual drug design. Silverman puts almost all of this material in about 70 pages as Chapter 2 and then doesn't talk much about it afterwards. (n.b. these comments apply to the 3rd edition of Patrick which is about double the size of the 2nd edition). YMMV

I can't fault the suggestion to read the primary literature, but if you are trying to make sense of the less obvious tools referenced to avoid the "here there be dragons" mindset, a good textbook makes getting into that literature a lot easier.


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20. Wavefunction on November 14, 2007 11:44 AM writes...

Echoing #17, SIlverman is indeed excellent. The best med chem intro I have come across is Graham Patrick.

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