Summary for 8W0R
| Entry DOI | 10.2210/pdb8w0r/pdb |
| EMDB information | 43712 |
| Descriptor | 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase, 1-methyl-1'-[(oxan-4-yl)methyl]-5-(trifluoromethyl)spiro[indole-2,4'-piperidin]-3(1H)-one (2 entities in total) |
| Functional Keywords | emopamil-binding protein isomerization protein structure complex, structural protein, isomerase-inhibitor complex, isomerase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 55608.58 |
| Authors | |
| Primary citation | Dorel, R.,Sun, D.,Carruthers, N.,Castanedo, G.M.,Ung, P.M.,Factor, D.C.,Li, T.,Baumann, H.,Janota, D.,Pang, J.,Salphati, L.,Meklemburg, R.,Korman, A.J.,Harper, H.E.,Stubblefield, S.,Payandeh, J.,McHugh, D.,Lang, B.T.,Tesar, P.J.,Dere, E.,Masureel, M.,Adams, D.J.,Volgraf, M.,Braun, M.G. Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation. J.Med.Chem., 67:4819-4832, 2024 Cited by PubMed Abstract: The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential therapeutic approach for treating multiple sclerosis. Herein, we describe the discovery and optimization of brain-penetrant, orally bioavailable inhibitors of EBP. A structure-based drug design approach from literature compound led to the discovery of a hydantoin-based scaffold, which provided balanced physicochemical properties and potency and an improved safety profile. The long half-lives of early hydantoin-based EBP inhibitors in rodents prompted an unconventional optimization strategy, focused on increasing metabolic turnover while maintaining potency and a brain-penetrant profile. The resulting EBP inhibitor demonstrated strong target engagement in the brain, as illustrated by the accumulation of EBP substrate zymostenol after repeated dosing. Furthermore, compound enhanced the formation of oligodendrocytes in human cortical organoids, providing additional support for our therapeutic hypothesis. PubMed: 38470227DOI: 10.1021/acs.jmedchem.3c02396 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.8 Å) |
Structure validation
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