9EP8
Crystal structure of ROCK2 in complex with a 8-(azaindolyl)-benzoazepinone inhibitor
This is a non-PDB format compatible entry.
Summary for 9EP8
| Entry DOI | 10.2210/pdb9ep8/pdb |
| Descriptor | Rho-associated protein kinase 2, 8-(azaindolyl)-benzoazepinone, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | rock2, kinase inhibitor, 8-(azaindolyl)-benzoazepinone, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 185076.23 |
| Authors | Pala, D.,Clark, D.,Pioselli, B.,Accetta, A.,Rancati, F. (deposition date: 2024-03-18, release date: 2024-09-25, Last modification date: 2024-10-02) |
| Primary citation | Pala, D.,Clark, D.,Edwards, C.,Pasqua, E.,Tigli, L.,Pioselli, B.,Malysa, P.,Facchinetti, F.,Rancati, F.,Accetta, A. Design and synthesis of novel 8-(azaindolyl)-benzoazepinones as potent and selective ROCK inhibitors. Rsc Med Chem, 2024 Cited by PubMed Abstract: We report the characterization of potent and selective ROCK inhibitors identified through a core-hopping strategy. A virtual screening workflow, combining ligand- and structure-based methods, was applied on a known series of ROCK inhibitors bearing an acetamido-thiazole scaffold. The most promising replacement of the central core was represented by a benzoazepinone ring, which was selected as a starting point for a subsequent chemical exploration. The overall design approach exploited previous SARs available for congeneric series and crystallographic information to optimize the hinge-binding group as well as the terminal aromatic moiety interacting with the glycine-rich loop. The introduction of elongated and flexible charged groups led to compound 15, which exhibited sub-nanomolar potencies in biochemical and cellular assays, as well as a remarkable selectivity over PKA. HDX studies not only supported the postulated binding mode of compound 15 but also confirmed the crucial role of specific ROCK peptide segments in driving ligand selectivity. PubMed: 39297059DOI: 10.1039/d4md00313f PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.63 Å) |
Structure validation
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