In the last post, I was wondering why the BI guys did not use any docking to conjecture the binding mode of their new p38 inhibs. While docking is not a foolproof predictor, it can shed light on possible anomalous modes. Particularly interesting was this observation about the benzothiophene sulfur reversing its trans preference to become cis to the adjacent amide oxygen. This counterintuitive observation was later explained by alluding to the glutamate that would have had an unfavourable electrostatic interaction with the sulfur had it been trans to the oxygen. The observation was revealed by the crystal structure. However, before the crystal structure was obtained, they went through the design and synthesis of two compounds based on the reasonable hypothesis that the sulfur would be trans. It was only after their puzzlement with the failure of these designed compounds that the situation became clear through crystallography.
Well, the observation is also revealed by Glide XP docking, and I think this could have saved them some time. I first duplicated the X-ray pose of the earlier BIRB compound in p38 (1KV2 PDB id), and then docked the new compound in. The result; the binding score was still good, if not as good as for BIRB. But the important fact was that all the top 5 docking poses from Glide indicated the sulfur to be cis to the oxygen and away from the Glu, just as in the crystal. In fact, even the fragment docked in the same position as the crystal structure indicated, with the sulfur cis. Not totally surprising if electrostatic interactions are well parametrized and recognised by the scoring function. A further advancement where polarization effects are taken into account during docking would help a lot (This is in the works)
This was one case in which docking could have said basically the same thing that the crystal structure did. In this case, docking could have saved them the design and synthesis of two extra compounds based on a misleading hypothesis, and perhaps additional head-scratching validated by crystallography. On a related note, Glide is pretty well-parametrized on a couple of kinases, including Lck, CDK2, and p38.
Subrahmanyan Chandrasekhar: A study in fortitude and rigor
2 days ago in The Curious Wavefunction