Summary for 8TYF
| Entry DOI | 10.2210/pdb8tyf/pdb |
| Descriptor | Plasmepsin V, 2-acetamido-2-deoxy-beta-D-glucopyranose, (2E,4aR,7aS)-6-[(3M)-3-(2-chlorophenyl)pyridin-2-yl]-7a-(2,5-difluorophenyl)-2-imino-3-methyloctahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one, ... (5 entities in total) |
| Functional Keywords | plasmepsinix, plasmepsinx, inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Plasmodium vivax Sal-1 |
| Total number of polymer chains | 1 |
| Total formula weight | 53654.91 |
| Authors | Hodder, A.N.,Scally, S.W.,Czabotar, P.E.,Cowman, A.F. (deposition date: 2023-08-25, release date: 2024-08-28, Last modification date: 2025-09-10) |
| Primary citation | Hodder, A.N.,Sleebs, B.E.,Adams, G.,Rezazadeh, S.,Ngo, A.,Jarman, K.,Scally, S.,Czabotar, P.,Wang, H.,McCauley, J.A.,Olsen, D.B.,Cowman, A.F. Structure-activity analysis of imino-pyrimidinone-fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors. Febs J., 292:2843-2864, 2025 Cited by PubMed Abstract: A library of known aspartic protease inhibitors was screened to identify compounds that inhibit plasmepsin V from Plasmodium vivax. This screen revealed compounds with an imino-pyrimidinone-fused pyrrolidine (IPF) scaffold that exhibited sub-micromolar inhibitory activity against plasmepsin V. Further screening of IPF analogs against the related aspartic protease plasmepsin X showed inhibitory activity, while a third aspartic protease, plasmepsin IX, was not significantly inhibited. Modifications to the P1 biaryl region of the IPF scaffold differentially modulated inhibition of both plasmepsin V and X. Notably, analogs with potent plasmepsin X inhibitory activity successfully blocked the growth of Plasmodium falciparum in vitro. X-ray structures of IPF analogs in complex with plasmepsin V provided insights into their binding mode and revealed avenues to further improve IPF potency and selectivity between plasmepsin V and X. This understanding of how these compounds interact with the active sites of plasmepsin V and X will serve as a foundation for the future design of dual inhibitors targeting these proteases. PubMed: 40035447DOI: 10.1111/febs.70038 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.59 Å) |
Structure validation
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