In case you missed it, I spoke at the ACS on Sunday. It was in a computational session looking at designing libraries and I am pretty sure I was the only non compchemist. It was about all the problem compchemists have caused in library design. My talk was even live tweeted by Ash (@curiouswavefn) and was well received. So, looking at the next paper in my queue, its a computational-focused paper. So, After spending several hours on a Sunday listening to compchemists, have I softened?
This paper is the subject of today's post. It is an extension of this paper which describes their virtual screen. From a 2 million compound virtual screen, they tested 17 compounds in vitro leading to 2 micromolar compounds. This paper is the story of the most potent of the two micromolar compounds. The target is CREBBP, which is another in the long line of epigenetic targets. Compound A was one of the original in silico actives that was tested. Three analogs were obtained and tested (B-D).
|Figure 1. Original active, A. Analogs B-D. Common structural motif is shown in blue.|
Compound B was the most potent and become the focus of their optimization efforts. Of course, my eyes are drawn to that potential michael acceptor, but the authors dismiss it based upon their docking results: the only alkylatable residue in the area of its putative binding is well buried. It is a moot point anyway because they were able to replace it with a isopthalate group and increase potency by 5x, 0.9uM (Compound 6). Interestingly,the potency of 6 is different depending on the assay used: 0.8 um in a competition binding assay and 8.7uM in a TR-FRET assay.
|Figure 2. Compound 6|
They then performed some gobbledy-gook MD calculations (finite-difference Poisson, warning PDF) in order to evaluate the electrostatic contribution of the polar contribution to binding of 6 and 7. Compound 6 had more favorable electrostatic interactions (0.8 kcal/mol) than 7, which had more favorable van der Waals interactions (1.4 kcal/mol). With this crucial information AND the crystal structure in hand, they then explored additional chemical space.
Despite the authors' claim, I don't think they actually improved the potency significantly. Compound 6 is 8 uM in the TR-FRET assay and the best compounds they claim are 1 or 2 uM. I really have to call monkeyshines here. They use the different assays interchangeably, yet never explain the one is used for what purpose. Its cherry picking values. When talking about selectivity, they switch to using thermal shift values. And we all know the value of that. So, I find it hard to believe their "most potent" this or "selectivity" that. The title of the paper includes "nanomolar", but that is only in one assay. That's like saying I can run a 6 minute mile, since I did it once under optimum conditions. Honestly, my typical times (WAY back when) were more 8:30 miles. That honesty in data reporting. Since they obviously had access to different assays, why weren't all compounds run in one, or optimally both. I don't see that the MD calculations had any positive impact. Maybe its the heat, but this paper is a not a sham, but definitely full of deceptive advertising.