About this Author
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: Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Clamping Down, or Loosening Up? | Main | And Another Thing. . . »

September 29, 2005

The Hazards of Molecular Modeling

Email This Entry

Posted by Derek

A comment to the last post really gave me the shivers:

"I like to think of modelling as the "silent killer". It is easy to rely on it for quick answers, and easy to forget that there is no substitute for an actual experiment. . .

I remember asking a fellow scientist if a particular molecule performed as hypothesized, the response was: " I don't know. It did not dock well into the enzyme, so I didn't make it."

I've made this point before, but it needs to be made again: molecular modeling is not reality. Most models are not that good, or only good around a limited group of rather similar compounds. If you as a medicinal chemist are crossing out easy-to-make compounds in unexplored chemical space just because the software doesn't like it, you are handcuffing yourself and tying your thumbs together. Stop it, stop it for your own good, or you may never discover anything unexpected or useful.

"The silent killer": I like that phrase a lot. I get the occasional testy e-mail from the computational types when I talk like this, but I'm sticking to my beliefs here. Molecular models based on numerous high-resolution X-ray structures are, I think, sort of useful, sometimes. Models based on only one X-ray structure are to be approached with great caution. And binding models that are just calculated up de novo should be treated as hazardous to your scientific health, unless you have a great deal of evidence to make you think otherwise.

OK, you silicon jockeys, go ahead and flood my in-box. I've earned it.

Comments (7) + TrackBacks (0) | Category: In Silico


1. Tim Mayer on September 30, 2005 9:12 AM writes...

A famous scientist once said: "Running data through a computer does not consitute a meaningful experiment." I couldn't agree more.

Permalink to Comment

2. Milo on September 30, 2005 11:42 AM writes...

I think that models are good at helping to formulate explanations: Why is this NOT binding? Is there a charged residue nearby? Unfavorable sterics? I use xray structures quite a bit in this regard, especially on my present project.

I am always sure to tell people that I am trying to explain REAL DATA!!

I like the folks who claim that: "If we had a bigger computer, we could screen 10^10 molecules to find out which ones are good (or bad)." Being a postdoc at a university, I tend to here this a lot. It always makes me smile.

Although, you have to admit that the pictures are pretty, especially the QSAR ones in J. Med. Chem. :-)

Permalink to Comment

3. Ronald Cook on September 30, 2005 3:41 PM writes...

As one who does molecular modeling in a non-biomedical field I agree with your post. Modeling should guide not decide. Over the years I have found that modeling is at it's best when used to understand the results of experiments, but not when it is done instead of the expriment

Ronald Cook

Permalink to Comment

4. Michelle Francl on September 30, 2005 6:18 PM writes...

As a developer and user of in silico methods let me add to the flood. Bravo! It's not reality by a long stretch, and I work hard to remind my students (and organic and medicinal colleagues) that good modeling (even models that include or are QM based) is a help to thinking through a problem, but in most cases can't definitely answer the problem.

The caveat is that very careful, high level QM methods can provide answers that are comparable to (and capable of uncovering the errors in) experiments.

Permalink to Comment

5. Jim Harris on October 1, 2005 8:12 AM writes...

In addition to the above concerns, companies purchase tox and ADME packages, and I worry that some people actually use them. Why is management allowing this to go on?

Permalink to Comment

6. Elia Diodati on October 1, 2005 7:22 PM writes...

Dr. "famous scientist" is attributed to lots of things. It would be nice to discover who he/she is, and why, despite the reputed fame, we don't know his/her identity.

As a student in a computational chemistry group, I couldn't agree with you more. Many users of modeling software forget/don't realize that a model is only as good as its premises; models that "understand" quantum mechanics are better than those which do not. The flip side, of course, is that the former take a long time to compute with to come up with an answer.

Permalink to Comment

7. Drug development on August 17, 2008 5:57 AM writes...

It's good to see that there are people with basic logic in this field that know to distinguish between the facts and the way to get to the facts.

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry