Monday, 20 August 2012

QSAR: Nailed to its perch?

I must confess that I’ve never been a big fan of QSAR. When I started in Pharma 24 years ago, QSAR was seen as as something that would solve all our problems and, over the years, a number of other panaceas would follow in its wake. I find it useful to classify molecular design as either hypothesis-driven or prediction-driven and will discuss this a bit more in a future post. QSAR fits into the prediction-driven category and, to get you thinking a bit about the subject, I'll share a couple of slides from my RACI talk last December.

So EuroQSAR is due to happen again and this time there'll be a session to commemorate QSAR's founding father Corwin Hansch, who died last year.  So will 'Grand Challenges for QSAR' deliver?  Were I going to be there, I'd be checking out Maggiora's talk (Activity Cliffs, Information Theory, and QSAR) since people in the field really need to start thinking more about QSAR in terms of relationships between structures.  Although it's not part of the Hansch session, I'd also be checking out 'The Power of Matched Pairs in Drug Design' by my good friend (and former colleague) Jonas Boström since Matched Molecular Pairs represent one way to recognise and articulate relationships between structures.  And of course I wouldn't miss the Hansch Awardee's talk, the title of which reminded me of an Austrian who struggled, although you won't find that one stocked in the local book shops...

I would like to have seen something on training set design and validation in the 'Grand Challenges' session.  Generally building and validating multivariate models work best when the compounds are distributed evenly in the relevant descriptor space.  Clustering in descriptor space can result in validation giving an optimistic view of model quality and that's one way to end up over-fitting yout data.  Maybe this was one Grand Challenge that the Organising Committee just didn't have the stomach for...

So that's all from me for now.  Why not print out 'QSAR: dead or alive?' (it infuriates those who would seek to lead your opinion) to read on the plane and think up some nasty questions on validation for the experts while waiting in Passkontrolle?

Literature Cited

Doweyko, QSAR: dead or alive? JCAMD 2008, 22, 81-89 DOI

Thursday, 9 August 2012

Lipophilicity and Pharmacological Promiscuity

We often hear and read that pharmacological promiscuity is strongly correlated with lipophilicity and it's often a good idea to check that the dogma matches the data. I set up a poll (which closed just over a week ago) for the LinkedIn FBDD group that asked the question:

Is pharmacological promiscuity strongly correlated with lipophilicity?

And the responses were: Yes (43 votes), No (5 votes) and Don't Know (2 votes)

Although the poll is now closed, we're still discussing the results so why not come and join the fun.