17 April 2012

Sometimes Your Compound Sucks

Folks, let me wax grouchy. But, first, let me explain. My kids (10 and 7) play sports. I try to inculcate them with a sense of fairplay and sportsmanship. From their first game, I have always said to them: two rules to playing sports. 1. Never blame the refs (umps). 2. Never blame the equipment. It has gotten me through a lot of losses, hurt feelings, and it generally makes me feel like a good dad. I then take the money I am putting away for when they need therapy later in life for all the bad things I will/have done and buy beer. Trust me, this will come into play in at the end.
I have been trying to figure out how to review this paper from Bastien et al. It hasn't been easy. The kinder gentler version of Teddy is just not a hit. Go figure. This paper is aimed at delivering J. Med Chem. quality data derived from fragments on a mutant DHFR. DHFR is a long time drug target and is currently used in many approved therapies.
The paper all started out so well, with description of the fragment library, you know, fragments, "generally comprise[d} cycles -- often aromatic-- and were generally of an elongated structure." Seriously, in J. Med. Chem., they described their fragment library that way. There is no supplementary information.
With this excellently characterized fragment library, the screened all 100 compounds (what a herculean effort) and found 7 compounds in the high micromolar to millimolar range.
This is what they found...oh, and no inhibition in the biochemical assay for follow up compounds 1a, 4a,b,c,5a, and 6a. The depth of the SAR startled me. They did extensive SAR which led to this:
Now, starting from fragments which had pretty decent ligand efficiency, there were able to generate these horrendous monsters, with absolutely revolting LE. They then point out that these are "poorly optimized compounds." DUH.
They then did docking of the molecules and it shows that these symmetrical molecules for a U shaped molecule and suggest that intermolecular stacking may occur in solution. They then point out that this may be due to limitation in the docking software. Then tried to soak (9) into crystals, but there was a change in the active site pore electron density. And, again another excuse, "The pore lies on the crystallographic symmetry axes, combined with the fact that the ligand did not appear to be present at full occupancy, it prove impossible to interpret the electron density." YET, in the very next sentence, seriously the very next one, "From what could be seen, the density was not consistent with the U-shaped conformation of compound 9 as suggested by the docking results, but the poor quality of the electron density PRECLUDES DRAWING CONCLUSIONS [emphasis mine] on the actual bound conformation of the inhibitor."
So, now at this point, my brain literally explodes like this:
One more highly quotable line is: "Notwithstanding the precise mode of binding, symmetry appears to play a key role in binding in selectivity. " I assure you all I am NOT making this up.

There may be some redeeming social value in the paper, but I give up in finding it. Bastien et al., stop blaming the refs and the equipment!!!


Dan Erlanson said...

I do think it’s nice that more academics are using and publishing on fragments, and while I may not be quite as “grouchy” as Teddy I do think he raises important points. One additional point I’d like to raise is that more experiments need to be done to demonstrate that the compounds (and possibly even the fragments themselves) are bona fide inhibitors. Small heterocycles, even with carboxylic acid moieties, have repeatedly been shown to form aggregates at high concentrations (see for example here and here), which can overwhelm true positives in functional assays.

According to the experimental section the researchers did not have detergent in their assay. Adding detergent is one of the most straightforward ways to prevent aggregation, so inhibitors found in the absence of detergent require further scrutiny. In this case, the fact that the compounds show steep Hill slopes is also consistent with aggregation. Although the compounds show some evidence of competition with both substrate and cofactor, in my opinion these experiments need to be done at more than two concentrations to truly determine their mode of inhibition.

I don’t mean to pick on these folks – I’ve met the PI and I think she’s a first-rate scientist. Perhaps these are legitimate DHFR inhibitors. However, it’s all too easy to be misled, and I think everyone would be well-served to follow the advice of Chris Austin: “Every data point we generate is an artifact until proven otherwise.”

Dr. Teddy Z said...

This was also highlighted here: http://pipeline.corante.com/archives/2012/04/18/how_do_these_things_get_published.php
I am not the only appalled at this paper.

Anonymous said...

" I’ve met the PI and I think she’s a first-rate scientist."

I appreciate that, and I have often felt that way about scientists whom I have met.

Then I read one of their papers, and the rubber meets the road.

This is not the work of a first-rate scientist(s). This is crraap.

Anne said...

Actually, there is supplemental information, with structures for all the fragments tested. It's linked on the ACS page. That said, yeah... no good.

Anonymous said...

J Med Chem has gone to shit over the years. Look at who is at the helm, they are self serving idiots. They still publish crap like this, crap full of aggregators and PAINS all the time, and crap that was sent in from companies like Schrodinger, who don't do any due diligence and who change the predictions after they find out the answers.

Basically, if you are on the accepted list of scientists and you persist, you'll get your paper published. Because honestly, how much lower can you go? Some docking papers get sent to JCIM to die, but others basically die in J Med Chem. And everybody needs every paper to be accepted.