9D7N
Human p38alpha MAP Kinase in complex with 1-Isobutyl-1H-indazole derivative; OSF267
This is a non-PDB format compatible entry.
Summary for 9D7N
| Entry DOI | 10.2210/pdb9d7n/pdb |
| Descriptor | Mitogen-activated protein kinase 14, 5-[(2,4-difluorophenyl)methyl]-N-[2-(dimethylamino)ethyl]-1-(2-methylpropyl)-1H-indazole-6-carboxamide, 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE, ... (4 entities in total) |
| Functional Keywords | p38, kinase, inhibitor, complex, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40438.32 |
| Authors | Brunzelle, J.S.,Shuvalova, L.,Benetik, S.F.,Roy, S.M.,Watterson, D.M.,Gobec, S. (deposition date: 2024-08-16, release date: 2025-09-24) |
| Primary citation | Ferjancic Benetik, S.,Proj, M.,Knez, D.,Kosak, U.,Meden, A.,Krajsek, K.,Pislar, A.,Horvat, S.,Svajger, U.,Tesic, N.,Pulkrabkova, L.,Soukup, O.,Skarka, A.,Andrys, R.,Brazzolotto, X.,Igert, A.,Nachon, F.,Dias, J.,Detka, J.,Gdula-Argasinska, J.,Wyska, E.,Szafarz, M.,Manik, A.,Plachtij, N.,Musilek, K.,Salat, K.,Obreza, A.,Gobec, S. Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38 alpha Mitogen-Activated Protein Kinase Inhibitors. J.Med.Chem., 68:17378-17411, 2025 Cited by PubMed Abstract: The currently approved drugs for the treatment of Alzheimer's disease (AD) fail to address its interconnected pathological processes. Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) offers an innovative dual approach to mitigate two major drivers of neurodegeneration in AD: cholinergic deficit and neuroinflammation. Using structure-based drug design and a library of known p38α MAPK inhibitors, we developed first-in-class, selective dual BChE/p38α MAPK inhibitors with balanced activity against both targets. The X-ray crystal structures of the two most promising molecules bound to both enzymes were solved. Those ligands effectively reduced the production of proinflammatory markers in vitro and ex vivo in phytohemagglutinin/lipopolysaccharide neuroinflammation models. Remarkably, these compounds also significantly improved cognition in scopolamine- and lipopolysaccharide-induced models of cognitive dysfunction in mice. Because our dual-acting inhibitors target both the symptoms and the underlying neuropathology, they offer an innovative and comprehensive strategy to combat AD. PubMed: 40779804DOI: 10.1021/acs.jmedchem.5c00933 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.973 Å) |
Structure validation
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