7PIF
Protein kinase A catalytic subunit in complex with PKI5-24 and EN086
Summary for 7PIF
| Entry DOI | 10.2210/pdb7pif/pdb |
| Descriptor | cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase inhibitor alpha, 5-[3-[4-(aminomethyl)oxan-4-yl]phenyl]-2-azanyl-benzenecarbonitrile, ... (6 entities in total) |
| Functional Keywords | protein kinase, ligand complex, transferase |
| Biological source | Cricetulus griseus (Chinese hamster) More |
| Total number of polymer chains | 2 |
| Total formula weight | 43881.17 |
| Authors | Glinca, S.,Mueller, J.M.,Ruf, M.,Merkl, S. (deposition date: 2021-08-19, release date: 2022-09-21, Last modification date: 2024-10-16) |
| Primary citation | Muller, J.,Klein, R.,Tarkhanova, O.,Gryniukova, A.,Borysko, P.,Merkl, S.,Ruf, M.,Neumann, A.,Gastreich, M.,Moroz, Y.S.,Klebe, G.,Glinca, S. Magnet for the Needle in Haystack: "Crystal Structure First" Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces. J.Med.Chem., 65:15663-15678, 2022 Cited by PubMed Abstract: Fragment-based drug discovery (FBDD) has successfully led to approved therapeutics for challenging and "undruggable" targets. In the context of FBDD, we introduce a novel, multidisciplinary method to identify active molecules from purchasable chemical space. Starting from four small-molecule fragment complexes of protein kinase A (PKA), a template-based docking screen using Enamine's multibillion REAL Space was performed. A total of 93 molecules out of 106 selected compounds were successfully synthesized. Forty compounds were active in at least one validation assay with the most active follow-up having a 13,500-fold gain in affinity. Crystal structures for six of the most promising binders were rapidly obtained, verifying the binding mode. The overall success rate for this novel fragment-to-hit approach was 40%, accomplished in only 9 weeks. The results challenge the established fragment prescreening paradigm since the standard industrial filters for fragment hit identification in a thermal shift assay would have missed the initial fragments. PubMed: 36069712DOI: 10.1021/acs.jmedchem.2c00813 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.395 Å) |
Structure validation
Download full validation report
