4WOT: ROCK2 IN COMPLEX WITH 1426382-07-1

ROCK1 and ROCK2 play important roles in numerous cellular functions, including smooth muscle cell contraction, cell proliferation, adhesion, and migration. Consequently, ROCK inhibitors are of interest for treating multiple indications including cardiovascular diseases, inflammatory and autoimmune diseases, lung diseases, and eye diseases. However, systemic inhibition of ROCK is expected to result in significant side effects. Strategies allowing reduced systemic exposure are therefore of interest. In a continuing effort toward identification of ROCK inhibitors, we here report the design, synthesis, and evaluation of novel soft ROCK inhibitors displaying an ester function allowing their rapid inactivation in the systemic circulation. Those compounds display subnanomolar activity against ROCK and strong differences of functional activity between parent compounds and expected metabolites. The binding mode of a representative compound was determined experimentally in a single-crystal X-ray diffraction study. Enzymes responsible for inactivation of these compounds once they enter systemic circulation are also discussed.
PDB ID: 4WOTDownload
MMDB ID: 129083
PDB Deposition Date: 2014/10/16
Updated in MMDB: 2015/06
Experimental Method:
x-ray diffraction
Resolution: 2.93  Å
Similar Structures:
Biological Unit for 4WOT: dimeric; determined by software (PISA)
Molecular Components in 4WOT
Label Count Molecule
Proteins (2 molecules)
Rho-associated Protein Kinase 2(Gene symbol: ROCK2)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB