Readers of a
certain age may fondly remember the interviews with Dr. Noitall that used to
enliven the pages of Science. Sadly, he
died a few years back. But his cousin, Dr. Saysno, is still very much alive. Practical Fragments caught up with him
at a recent conference in Shutka.
Practical Fragments (PF):
Dr. Saysno, you've stated that experts should never be trusted.
Dr. Saysno (DS): Niels
Bohr defined an expert as a person who has made all the mistakes that can be
made in a very narrow field. If someone has made every possible mistake, how
could you possibly trust them?
PF: But don't you think
they may have learned from their mistakes?
DS: Balderdash! Hegel was
right: the only thing we learn from history is that we learn nothing from
history.
PF: What's your opinion of
ligand efficiency (LE)?
DS: Ligand efficiency is
an abomination! It's mathematically invalid!
Worse,
determining the free energy of binding from a dissociation constant is not even
wrong: if you change your definition of standard state, you can make ΔG° any
positive or negative number you want. Just how relevant do you think your definition of standard state is on the surface of Venus? Or Pluto?
For the same
reason, pH is utterly meaningless. You really ought to throw out your pH paper,
not to mention your pH meters, since they all assume an arbitrary reference
state.
PF: But what about all the
researchers who find pH and LE useful?
DS: Usefulness is the last
refuge of the scoundrel!
Look, many of
the best selling drugs on the market are antibodies, and when you calculate
their ligand efficiencies, they are close to zero. How can you have a metric
that doesn't work on some of the most important drugs out there?
I only believe
in equations that are universal and apply in all situations, unsullied by the
physical world. Anything that involves standard states is just mumbo-jumbo.
PF: What do you think of pan-assay
interference compounds, or PAINS?
DS: Now that’s a topic that
really gets my blood boiling! PAINS were defined on the basis of just six
assays. Six assays I tell you!!! [DS
vigorously pounds his shoe on the desk.] Just because something hits six
assays – or six hundred for that matter – doesn’t mean it will hit the six
hundred and first!
PF: But aren't there some
chemical substructures that are so generically reactive they should never be
used in probes?
DS: Nothing is universal!
All molecules are unique, like little snowflakes. If a compound comes up as a
hit in your assay, by all means publish it as a chemical probe in the best
possible journal, and try to encourage suppliers to start selling it so other
people can use and cite your brilliant discovery.
No one has a
right to criticize your molecule unless they test it against every single
protein in the human body and show that it hits all of them.
When the
revolution comes, the imperialist PAINS stooges will be swept into the dustbin
of history along with the lackeys of ligand efficiency!
PF: So if you don't trust
experts, you don't like metrics, and you can't make generalizations, how can we
move forward in science short of deriving every result ourselves from first
principles?
DS: That's simple: just ask
me!
Hilarious. Thanks :)
ReplyDeleteBut we must go further if we are to stake the vampire of molecular obesity. First we must assimilate the teachings of the Budapest School Of Unitless Thermodynamics and embrace the catechism of the Anti-Fat Anti Flat Movement. We must ensure that results of data analysis never contradict the Truth as defined by Medicinal Chemistry Leaders (including those now employed as consultants). We must accept that Road to Salvation is paved with Thermodynamic Proxies and that disruption by Baysesian Models on phones represents a seminal advance in the quest for perfect compound quality. Finally, mention singlet oxygen only under PAIN of excommunication and declare unclean thoughts to be Literature Pollution.
ReplyDeleteI love it!
ReplyDeleteGood April 1 joke.
ReplyDeletePersonally I think Dr. Saysno raises some important points. Unlike deterministic fields such as engineering, drug discovery rarely has absolute rules.
ReplyDeleteThat said, even weak correlations can sometimes yield valuable guidelines. It is important that, while inveighing against the overly strict application of rules, one does not make the opposite mistake of asserting that even flawed rules have no predictive value in certain situations.
Paul Leeson recently put it nicely:
Drug discovery is extremely difficult even within the Ro5, where drugs are tiny islands in a vast shark-infested ocean of chemical space. So why move to another vast, even less charted ocean where the islands are much rarer and the sharks are larger and fiercer?
You may have good reasons for going there: glorious treasure sometimes awaits those who overcome fierce guardians. But keep your eyes open, and don't underestimate the risks.
Greetings from the Molecular Simpleton, currently in West Wales for a few days of R&R. It's been a long time since I was sufficiently stimulated by good blog dialogue to return to the airways although I enjoy very much this and similar excellent blogs. Today is actually 30 years since I first made footfall at a certain molecule factory in Greenford (later transported to Hertfordshire), having refused to start on April 1st on account of a recent enforced exit from another molecule factory in High Wycombe. You may recall that when life got to complex for the Simpleton, he was forced to rant about Molecular obesity. This seemed a simple and useful thing to do, although he never envisaged what subsequent pedantic dialogue would arise from his and related treaties from esteemed colleagues on the woeful molecular inefficiencies of molecules that we aspire to be drugs. I have avoided the recent standard state debate out of deference to our forefathers who helped establish standard states and my own lack of mathematical pedantry, but on this fools day plus one, temptation has clearly got the better of me. There is a great saying which is attributed to Harry Day (Douglas Bader's commanding officer before the second world war) which goes something like: "Rules are for the obedience of fools and the guidance of wise men". If I can get guidance on a better molecule by dividing potency by MW then that is good enough for me, although I bet Bader wished he had obeyed flying rules on the day he did one too many stunts and ended up loosing both of his legs after crashing his plane! Hasta la vista, amigos!
ReplyDeleteHi Dan, good to see you continuing on the April Fools theme in the comments. I have learned the error of my ways and now believe that we should take no account of the strength of a trend when applying rules based on the trend. Also I was completely wrong about cut offs and should be excommunicated for suggesting that the seminal 4/400 rule simply reflects the arbitrary binning scheme used to categorize continuous data. I now ecstatically embrace the Wise Teachings of the Anti-Fat Anti-Flat Movement and exult in the Fundamental Truth of PFI, LELP and every other metric dreamed up by those wiser than me. I have belatedly come to realize that inflating correlations is a legitimate tool of the Visionary Thought Leader and that that I should never again criticize previous analysis when assessing ‘expert’ opinion. Please light the auto-da-fé now to cleanse my mind of these unclean thoughts and let us remember that The Leeson who spectacularly lost his Barings in the East Indies found salvation in Galway.
ReplyDeleteThe Molecular Simpleton may be amused to learn that promotions at a molecule factory in rural Cheshire were typically announced on April 1 and it took me some time to accept that I actually was a Principal Scientist (and that Our Leaders were not playing a cruel prank). I greatly enjoyed the reference to fighter pilot (and serial escapee) Bader who will be less familiar to many PF readers than the atoms-in-molecules Bader. The Molecular Simpleton may possibly remember the “Immelman’s Eindecker” Bunker Bulletin that had the unfortunate Max cursing his maintenance crew with, “Himmel! Der Spandau ist umsynchronisiert”. Twenty years of The Bunker Bulletin provided useful training for recent commentaries on the science of drug discovery although I have to admit that, in later years, the Bunker Bulletin was not always appreciated at Camp Chuckles whence wisdom flowed down a steep gradient in a north-westerly direction. The Bunker has since relocated to the Red Lion in Withington.
ReplyDeleteI have kept the aerial warfare theme going in the blogs and featured Malan’s Ten Rules For Air Fighting a couple of years ago. More recently, the Ju 87 Stuka (who else but the Germans would have thought of fitting a dive siren to their Stuka?) inspired the graphic for a post PAINS and I hope that readers in Germany and Austria appreciate the lengths that I went to in order to make that graphic legal to read in those countries. The Stuka graphic reminds me of Tael Gunnar who was a veteran of a number of sorties in Bunker airspace.
Still smiling at this post and it is already April 4th.
ReplyDelete