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!!!
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!!!
Posts
