In this paper, Li et al. report the first use of FBDD on Rho Kinase (ROCK). ROCK 1 and 2 are involved in several pathological diseases. These researchers (not in pharma) started their efforts aiming to target the hinge region of the ROCKs with 7 pyridyl containing compounds.
Luckily, Cpd 22 (with the new hinge binder) had similar activity to Cpd 18 (1.15 and 0.26 uM for Rock 1 and 2). 22 has a longer hinge binder, but shorter spacer than 18. 22 loses some of the hydrogen bonds seen in the modeling with 18 (N.B. this is NOT X-ray data), but gains of new ones are made. So it is a wash on net hydrogen bonding, but freer IP space. Cpd 18 was crystallized and as expected bound in the ATP site.
They then probed the chirality of the molecules, Cpd 24 (S configuration) was 75x more potent than Cpd 23 (R) for ROCK2, but only 5x for ROCK1. Fascinatingly, adding one more carbon to the spacer (Cpds 26 and 27) reverses this preference.
They then tested two pairs of compounds in cells (11/18 and 23/24). They showed activity in the cells that correlated with the in vitro data.
This is good example of academic drug design, but is raises some questions: 1. is selectivity for ROCK1 and ROCK2 important, 2. are these compounds in a clear IP space, 3. Why weren't the other compounds (like 23/24) crystallized, 4. What is the basis for the chiral preferences with a linker length dependence?
[Ed: sorry for funky font at the end...don't know why that is like that.]